Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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PYRIDAZINONES AS PARP7 INHIBITORS
FIELD OF THE INVENTION
The present invention relates to pyridazinones and related compounds which are
inhibitors of PARP7 and are useful in the treatment of cancer.
BACKGROUND OF THE INVENTION
Poly(ADP-ribose) polymerases (PARPs) are members of a family of seventeen
enzymes that regulate fundamental cellular processes including gene
expression, protein
degradation, and multiple cellular stress responses (M. S. Cohen, P. Chang,
Insights into the
biogenesis, function, and regulation of ADP-ribosylation. Nat Chem Blot 14,
236-243
(2018)). The ability of cancer cells to survive under stress is a fundamental
cancer
mechanism and an emerging approach for novel therapeutics. One member of the
PARP
family, PARP1, has already been shown to be an effective cancer target in
connection to
cellular stress induced by DNA damage, either induced by genetic mutation or
with cytotoxic
chemotherapy, with four approved drugs in the clinic and several others in
late stage
development ( A. Ohmoto, S. Yachida, Current status of poly(ADP-ribose)
polymerase
inhibitors and future directions. Onco Targets Ther 10, 5195-5208 (2017)).
The seventeen members of the PARP family were identified in the human genome
based on the homology within their catalytic domains ( S. Vyas, M. Chesarone-
Cataldo, T.
Todorova, Y. H. Huang, P. Chang, A systematic analysis of the PARP protein
family
identifies new functions critical for cell physiology. Nat Commun 4, 2240
(2013)). However,
their catalytic activities fall into 3 different categories ( S. Vyas et al.,
Family-wide analysis
of poly(ADP-ribose) polymerase activity. Nat Commun 5, 4426 (2014)). The
majority of
PARP family members catalyze the transfer of mono- ADP-ribose units onto their
substrates
(monoPARPs), while others (PARP1, PARP2, TNKS, TNKS2) catalyze the transfer of
poly-
ADP-ribose units onto substrates (polyPARPs). Finally, PARP13 is thus far the
only PARP
for which catalytic activity could not be demonstrated either in vitro or in
vivo.
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor
involved in regulating multiple cellular functions including proinflammatory
responses and
xenobiotic metabolism ( S. Feng, Z. Cao, X. Wang, Role of aryl hydrocarbon
receptor in
cancer. Biochim Biophys Acta 1836, 197-210 (2013); and B. Stockinger, P. Di
Meglio, M.
Gialitakis, J. H. Duarte, The aryl hydrocarbon receptor: multitasking in the
immune system.
Annu Rev Immunol 32, 403-432 (2014)). The AHR can be activated by a broad
number of
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ligands including endogenous tryptophan metabolites such as kynurenine ( C. A.
Opitz etal.,
An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor.
Nature
478, 197-203 (2011)) and certain polycyclic aromatic hydrocarbons such as
2,3,7,8-
tetrachlorodibenzo-p-dioxin (TCDD) ( K. W. Bock, Toward elucidation of dioxin-
mediated
chloracne and Ah receptor functions. Biochem Pharmacol 112, 1-5 (2016)).
Activation of the
AHR induces target gene expression including genes involved in metabolism such
as
cytochrome P4501A1 and P4501B1. Activation of AHR also leads to an increase in
the AHR
target gene, TCDD-inducible poly(ADP-ribose)polymerase (TIPARP, also referred
to as
PARP7), which functions as a negative regulator of certain AHR transcriptional
targets ( L.
MacPherson etal., Aryl hydrocarbon receptor repressor and TIPARP (ARTD14) use
similar,
but also distinct mechanisms to repress aryl hydrocarbon receptor signaling.
Int J Mol Sci 15,
7939-7957 (2014); and L. MacPherson etal., 2,3,7,8-Tetrachlorodibenzo-p-dioxin
poly(ADP-ribose) polymerase (TIPARP, ARTD14) is a mono-ADP-ribosyltransferase
and
repressor of aryl hydrocarbon receptor transactivation. Nucleic Acids Res 41,
1604-1621
(2013)).
PARP7 can also be regulated by other transcription factors and signaling
pathways
including androgen receptor ( E. C. Bolton et al., Cell- and gene-specific
regulation of
primary target genes by the androgen receptor. Genes Dev 21, 2005-2017
(2007)), platelet
derived growth factor ( J. Schmahl, C. S. Raymond, P. Soriano, PDGF signaling
specificity is
mediated through multiple immediate early genes. Nat Genet 39, 52-60 (2007))
and hypoxia
inducible factor 1 (N. Hao etal., Xenobiotics and loss of cell adhesion drive
distinct
transcriptional outcomes by aryl hydrocarbon receptor signaling. Mol Pharmacol
82, 1082-
1093 (2012)). The PARP7 gene is located on chromosome 3 (3q25) in a region
that is
frequently amplified in cancers of squamous histology
(http://www.cbioportal.org/index.do?session id=5aelbcde498eb8b3d565d8b2). A
genome-
wide association study identified 3q25 as susceptibility loci for ovarian
cancer suggesting a
role for PARP7 in this cancer type ( E. L. Goode etal., A genome-wide
association study
identifies susceptibility loci for ovarian cancer at 2q31 and 8q24. Nat Genet
42, 874-879
(2010)). PARP7 has multiple cellular functions. In the context of AHR
signaling PARP7
acts as a negative feedback mechanism to regulate the expression of P4501A1
and P4501B1 (
L. MacPherson etal., Aryl hydrocarbon receptor repressor and TIPARP (ARTD14)
use
similar, but also distinct mechanisms to repress aryl hydrocarbon receptor
signaling. Int J
Mol Sci 15, 7939-7957 (2014), and L. MacPherson etal., 2,3,7,8-
Tetrachlorodibenzo-p-
dioxin poly(ADP-ribose) polymerase (TIPARP, ARTD14) is a mono-ADP-
ribosyltransferase
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and repressor of aryl hydrocarbon receptor transactivation. Nucleic Acids Res
41, 1604-1621
(2013)). PARP7 has also been described to ADP-ribosylate liver X receptors
which leads to
the modulation of their transcriptional activity ( C. Bindesboll etal., TCDD-
inducible poly-
ADP-ribose polymerase (TIPARP/PARP7) mono-ADP-ribosylates and co-activates
liver X
receptors. Biochem J473, 899-910 (2016). During viral infection PARP7 can bind
to Sindbis
virus (SINV) to promote viral RNA degradation ( T. Kozaki et al.,
Mitochondrial damage
elicits a TCDD-inducible poly(ADP-ribose) polymerase-mediated antiviral
response. Proc
Natl Acad Sci USA 114, 2681-2686 (2017)). Also in the context of viral
infection, AHR-
induced PARP7 can interact with TBK1, a major kinase that is activated during
the onset of
pathogen-associated molecular pattern pathways leading to an activation of the
Type I
interferon response and antiviral immunity ( T. Yamada et al., Constitutive
aryl hydrocarbon
receptor signaling constrains Type I interferon-mediated antiviral innate
defense. Nat
Immunol 17, 687-694 (2016)). PARP7 was shown to ADP-ribosylate TBK1 which
prevents
its activation, thereby repressing the Type I interferon response.
Based on these results from viral infection one could hypothesize that cancer
cells can
use aberrantly expressed and/or activated PARP7 as a mechanism to evade the
host immune
system through suppression of the Type I interferons and thereby T cell
mediated antitumor
immunity. Indeed, in a recent genetic screen to identify tumor factors that
suppress T cell
activation PARP7 was identified as a hit (D. Pan etal., A major chromatin
regulator
determines resistance of tumor cells to T cell-mediated killing. Science 359,
770-775 (2018)).
PARP7 knockout in a mouse melanoma cell line was shown to increase the
proliferation and
activation of co-cultured T cells suggesting that PARP7 inhibition may be a
viable strategy to
activate T cell mediated tumor killing. Thus, there is an ongoing need for the
development of
PARP7 inhibitors.
SUMMARY OF THE INVENTION
The present invention is directed to a compound of Formula I:
0
X
HN
fl
A
or a pharmaceutically acceptable salt thereof, wherein constituent members are
defined
below.
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The present invention is further directed to a pharmaceutical composition
comprising
a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at
least one
pharmaceutically acceptable carrier.
The present invention is further directed to a method of inhibiting the
activity of
PARP7 comprising contacting a compound of Formula I, or a pharmaceutically
acceptable
salt thereof, with PARP7.
The present invention is further directed to a method of treating a disease or
disorder
in a patient in need of treatment, where the disease or disorder is
characterized by
overexpression or increased activity of PARP7, comprising administering to the
patient a
therapeutically effective amount of a compound of Formula I, or a
pharmaceutically
acceptable salt thereof
The present invention is further directed to a method of treating cancer in a
subject in
need thereof, the method comprising administering to the subject a
therapeutically effective
amount of an agent that inhibits PARP7 activity, such as a compound of Formula
I, or a
pharmaceutically acceptable salt thereof The present disclosure also provides
uses of the
compounds described herein in the manufacture of a medicament for use in
therapy. The
present disclosure also provides the compounds described herein for use in
therapy.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the effect of a compound of the invention on mean tumor volume in
animal models as described in Example B.
DETAILED DESCRIPTION
The present invention is directed to a compound of Formula I:
0
X
HN
N
A
or a pharmaceutically acceptable salt thereof, wherein:
X is Cl, Br, F, CH3, CF3, CF2H, CN, OCH3, ethyl, cyclopropyl, SCH3, or
isopropyl;
A is a group having a formula that is (A-1):
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/ R1 R2\ R5 R6 R7R8 /R11R1
rss<yi y2 ) f
3
q \ y r N __ 1_)-Z
a
3 \ R9 R1/3/
\R Rin
\ p
(A-1)
Yl, Y2, and Y3 are each independently selected from 0, S, NR, C(=0), C(=0)0,
C(=0)NRY, S(=0), S(=0)2, S(=0)NRY, S(=0)2NRY or NRYC(=0)NRY, wherein each RY
is
independently H, C1-4 alkyl, or C1-4 haloalkyl;
L is C1-3 alkylene, 0, S, NR, C(=0), C(=0)0, C(=0)NRY, S(=0), S(0)NR, or
NRYC(=0)NRY;
Z is H, Cyz, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN,
NO2, OW,
SW, C(0)R', C(0)NReRd, C(0)0W, OC(0)Rb, OC(0)NReRd, NReRd, NWC(0)Rb,
NWC(0)0W, NWC(0)NReRd, C(=NRe)Rb, C(=NRe)NReRd, NWC(=NRe)NReRd,
NWS(0)Rb, NReS(0)2R1), NReS(0)2NReRd, S(0)R', S(0)NReRd, S(0)2R1, and
S(0)2NReRd;
wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of Z
are each optionally
substituted with 1, 2, 3, 4, or 5 substituents independently selected from
Cyz, halo, CN, NO2,
ORd, SR', C(0)Rb, C(0)NReRd, C(0)0R', 0C(0)Rb, OC(0)NWRd, C(=NRe)NReRd,
NWC(=NRe)NReRd, NReRd, NReC(0)Rb, NReC(0)0W, NReC(0)NWRd, NReS(0)Rb,
NWS(0)2R1), NReS(0)2NReRd, S(0)R', S(0)NReRd, S(0)2R1, and S(0)2NReRd;
Cyz is selected from C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl,
and 4-10
membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4
substituents
independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, CN,
NO2, ORal, SRal, C(0)R', C(0)NRe'Rdl, C(0)0Ral, 0C(0)Rbl, OC(0)NRe1Rdl,
Q_NRei)NRciRdi, NRcic(_ NRei)NRciRcu, NRciRdi, Nw1c(0)Rbi, iNtc xmci
C(0)0Ral,
NW1C(0)NRciRdi, NRcisocoRbi, INK MC1
S(0)2Rbi, NRciS(0)2NRc1Rdl, sovr,b1,
S(0)NRciRdi,
S(0)2R, and S(0)2NRe1Rdl, wherein the alkyl, C2-6 alkenyl, and C2-6 alkynyl
are optionally
substituted with 1, 2, or 3 substituents independently selected from halo, CN,
NO2, ORal,
SRal, C(0)R', C(0)NRe'Rdl, C(0)0Ra1, 0C(0)Rbl, 0C(0)NR
awn, C(=NRel)NRe'Rdl,
NRc1c(-NRel)NRc1Rdl, NRc1Rdl, NRcicocoRbl, C 1
IN -K C(0)0Ral, NRC1C(0)NRC iRd
NRCiS (0)Rb NRC1S(0)2Rb NRC1S(0)2NRC1Rdl,
S (0)NRC iRd S(0)2R, and
S(0)2NRe1Rd1;
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Ring D is a monocyclic or polycyclic 4-10 membered heterocycloalkyl group
optionally substituted with 1, 2, or 3 groups independently selected from
halo, C1-6 alkyl, C2-6
alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa2, SR, c(o\R )b2,
C(0)NRc2Rd2,
C(0)OR, OC(0)Rb2, OC(0)NRc2Rd2, (-NRe2)NRc2Rd2, NRc2c (-NRe2)NRc2Rd2, NRc2Rd2,
NRc2c (0)Rb2, NRc2c (0)0Ra2, NRc2c (0)NRc2Rd2, NRosocoRb2, AK mc2
S(0)2Rb2,
NRc2s(0)2NRc2Rd2, so\-r=)Kb2,
S(0) NRc2-.xK d2,
S(0)2R12, and S(0)2NRc2Rd2, wherein the C1-6
alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1,
2, or 3 groups
independently selected from halo, CN, NO2, ORa2, sRa2, C(0)R'2, )
C(0)NRc2Rd2, C(0)OR,
OC(0)Rb2, OC(0)NRc2Rd2, (-NRe2)NRc2Rd2, NRc2c (-NRe2)NRc2Rd2, NRc2Rd2,
NRc2c (0)Rb2, NRc2c (0)0Ra2, NRc2c (0)NRc2Rd2, NRc2s(0)Rb2, xmc2
1NK S(0)2Rb2,
NRc2s(0)2NRc2Rd2, s(0\-.x)K b2,
S(0) NRc2-.xK d2,
S(0)2R'2, and S(0)2NRc2Rd2;
R2, R3, R4, R5, R6, R7, R8, R9, RI-9, RH, and R12 are each independently
selected
from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10
aryl, C3-7 cycloalkyl,
5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4
alkyl, C3-7
cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered
heterocycloalkyl-
C1-4 alkyl, CN, NO2, ORa3, SRa3, C(0)Rb3, C(0)NRc3Rd3, C(0)0Ra3, OC(0)Rb3,
OC(0)NRc3Rd3, NRc3Rd3, NRc3C(0)Rb3, NRc3C(0)0Ra3, NRc3C(0)NRc3Rd3,
C(=NRe3)Rb3,
C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3S(0)Rb3, NRc3S(0)2R13,
NRc3S(0)2NRc3Rd3,
S(0)R'3, S(0)NRc3Rd3, S(0)2R'3, and S(0)2NRc3Rd3; wherein said C1-6 alkyl, C2-
6 alkenyl,
C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered
heteroaryl, 4-10
membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl,
5-10 membered
heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of said
R2, R3, R4,
R5, R6, R7, R8, R9, R19, RH, and RH are each optionally substituted with 1, 2,
3, 4, or 5
substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6
alkynyl, C1-6
haloalkyl, CN, NO2, ORa3, SRa3, C(0)R'3, C(0)NRc3Rd3, C(0)0Ra3, OC(0)Rb3,
OC(0)NRc3Rd3, NRc3Rd3, NRc3C(0)Rb3, NRc3C(0)0Ra3, NRc3C(0)NRc3Rd3,
C(=NRe3)Rb3,
C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3S(0)Rb3, NRc3S(0)2R13,
NRc3S(0)2NRc3Rd3,
S(0)R'3, S(0)NRc3Rd3, S(0)2R13, and S(0)2NRc3Rd3;
or Rl and an RY group of V, together with the atoms to which they are attached
and
together with the atoms forming Yl form a 4-10 membered heterocycloalkyl ring,
optionally
substituted with 1, 2, or 3 substituents independently selected from halo, C1-
6 alkyl, C2-6
alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(0)Rb3,
C(0)NRc3Rd3,
C(0)0Ra3, OC(0)Rb3, OC(0)NRc3Rd3, NRc3Rd3, NRc3C(0)Rb3, NRc3C(0)0Ra3,
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NRc3C(0)1\1W3Rd3, C(=NRe3)Rb3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3,
NRc3S(0)Rb3,
NRc3S(0)2R13, NRc3S(0)2NRc3Rd3, \ Rb3,
) S(0)1\1Rc3Rd3, S(0)2R13, and
S(0)2NRc3Rd3;
or R7 and an RY group of Y3, together with the atoms to which they are
attached and
together with the atoms forming Y3 and together with the carbon atoms
substituted by R9,
Rth, RH, and R12, if present, form a 4-10 membered heterocycloalkyl ring,
optionally
substituted with 1, 2, or 3 substituents independently selected from halo, C1-
6 alkyl, C2-6
alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(0)Rb3,
C(0)NRc3Rd3,
C(0)0Ra3, OC(0)Rb3, OC(0)NRc3Rd3, NRc3Rd3, NRc3C(0)Rb3, NRc3C(0)0Ra3,
NRc3C(0)NRc3Rd3, C(=NRe3)Rb3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3,
NRc3S(0)Rb3,
NRc3S(0)2R1)3, NRc3S(0)2NRc3Rd3, S(0)R'3, ) S(0)1\1Rc3Rd3, S(0)2R13, and
S(0)2NRc3Rd3;
or Rl and R3 together with the carbon atoms to which they are attached form a
C5-lo
cycloalkyl ring or a 5-10 membered heterocycloalkyl ring, each optionally
substituted with 1,
2, or 3 substituents independently selected from halo, C1-6 alkyl, C2-6
alkenyl, C2-6 alkynyl,
C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(0)Rb3, C(0)1\1Rc3Rd3, C(0)0Ra3,
OC(0)Rb3,
OC(0)NRc3Rd3, NRc3Rd3, NRc3C(0)Rb3, NRc3C(0)0Ra3, NRc3C(0)NRc3Rd3,
C(=NRe3)Rb3,
C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3S(0)Rb3, NRc3S(0)2R13,
NRc3S(0)2NRc3Rd3,
S(0)R'3, S(0)1\1Rc3Rd3, S(0)2R13, and S(0)2NRc3Rd3;
or R3 and R5 together with the carbon atoms to which they are attached form a
C5-10
cycloalkyl ring or a 5-10 membered heterocycloalkyl ring, each optionally
substituted with 1,
2, or 3 substituents independently selected from halo, C1-6 alkyl, C2-6
alkenyl, C2-6 alkynyl,
C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(0)R'3, C(0)1\1Rc3Rd3, C(0)0Ra3,
OC(0)Rb3,
OC(0)NRc3Rd3, NRc3Rd3, NRc3C(0)Rb3, NRc3C(0)0Ra3, NRc3C(0)NRc3Rd3,
C(=NRe3)Rb3,
C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3S(0)Rb3, NRc3S(0)2R13,
NRc3S(0)2NRc3Rd3,
S(0)R'3, S(0)1\1Rc3Rd3, S(0)2R13, and S(0)2NRc3Rd3;
or R7 and R9 together with the carbon atoms to which they are attached form a
C5-10
cycloalkyl ring or a 5-10 membered heterocycloalkyl ring, each optionally
substituted with 1,
2, or 3 substituents independently selected from halo, C1-6 alkyl, C2-6
alkenyl, C2-6 alkynyl,
C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(0)R'3, C(0)1\1Rc3Rd3, C(0)0Ra3,
OC(0)Rb3,
OC(0)NRc3Rd3, NRc3Rd3, NRc3C(0)Rb3, NRc3C(0)0Ra3, NRc3C(0)NRc3Rd3,
C(=NRe3)Rb3,
C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3S(0)Rb3, NRc3S(0)2R13,
NRc3S(0)2NRc3Rd3,
S(0)R'3, S(0)1\1Rc3Rd3, S(0)2R13, and S(0)2NRc3Rd3;
or R9 and RH together with the carbon atoms to which they are attached form a
C5-10
cycloalkyl ring or a 5-10 membered heterocycloalkyl ring, each optionally
substituted with 1,
2, or 3 substituents independently selected from halo, C1-6 alkyl, C2-6
alkenyl, C2-6 alkynyl,
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C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(0)R'3, C(0)NRc3Rd3, C(0)0Ra3, OC(0)Rb3,
OC(0)NRc3Rd3, NRc3Rd3, NRc3C(0)Rb3, NRc3C1010Ra3, NRc3C(0)NRc3Rd3,
C(=NRe3)Rb3,
C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3S(0)Rb3, NRc3S(0)2R13,
NRc3S(0)2NRc3Rd3,
S(0)R'3, S1C0NRc3Rd3, S(0)2R'3, and S(0)2NRc3Rd3;
or R5 and R7 together with the carbon atoms to which they are attached and
together
with Y2 form a 5-10 membered heterocycloalkyl ring optionally substituted with
1, 2, or 3
substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6
alkynyl, C1-6
haloalkyl, CN, NO2, ORa3, SRa3, C101Rb3, C101NRc3Rd3, C1010Ra3, 0C101Rb3,
0C(0)NRc3Rd3, NRc3Rd3, NRc3C(0)Rb3, NRc3C1010Ra3, NRc3C(0)NRc3Rd3,
C(=NRe3)Rb3,
C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3S(0)Rb3, NRc3S(0)2R13,
NRc3S(0)2NRc3Rd3,
S(0)R'3, S1C0NRc3Rd3, S(0)2R'3, and S(0)2NRc3Rd3;
or R1 and R3 together form a double bond between the carbon atoms to which
they are
attached;
or R3 and R5 together form a double bond between the carbon atoms to which
they are
attached;
or R7 and R9 together form a double bond between the carbon atoms to which
they are
attached;
or R9 and RH together form a double bond between the carbon atoms to which
they
are attached;
or R9, R1 , RH, and R12 together form a triple bond between the carbon atoms
to
which they are attached;
each Re', Rb, RC, Rd, Ra1, Rbl, Rcl, Rdl, Ra2, Rb2, Rc2, Rd2, Ra3, Rb3, Rc3,
and Rd3 is
independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6
alkynyl, C6-10 aryl,
C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-
10 aryl-C1-4
alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-
10 membered
heterocycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6
alkynyl, C6-10 aryl, C3-7
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10
aryl-C1-4 alkyl,
C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10
membered
heterocycloalkyl-C1-4 alkyl of said Re', Rb, RC, Rd, Ra1, Rbl, Rcl, Rdl, Ra2,
Rb2, Rc2, Rd2, Ra3,
Rb3, Rc3, and Rd3 is optionally substituted with 1, 2, or 3 substituents
independently selected
from halo, C14 alkyl, C14 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, ORa7,
SRa7, C(0)Rb7,
C(0)NRc7Rd7, C1010Ra7, 0C101Rb7, 0C1CONRc7Rd7, NRc7Rd7, NRc7C(0)Rb7,
NRc7C(0)NRc7Rd7, NRc7C(0)0Ra7, C(=NRe7)NRc7Rd7, NRc7C(=NRe7)NRc3Rd7, s(c)Rb7,
S(0)NRc7Rd7, S(0)2R17, NRc7S(0)2R1)7, NRc7S(0)2NRc7Rd7, and S(0)2NRc7Rd7;
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or RC and Rd together with the N atom to which they are attached form a 4-7
membered heterocycloalkyl group optionally substituted with 1, 2, or 3
substituents
independently selected from CN, halo, C1-4 alkyl, C1-4 haloalkyl, C1-6
haloalkyl, C2-6 alkenyl,
C2-6 alkynyl, CN, OR a7, SRa7, C(0)Rb7, C(0)NRc7Rd7, C(0)0Ra7, OC(0)Rb7,
OC(0)NRc7Rd7,
NRc7Rd7, NRc7C(0)Rb7, NRc7C(0)NRc7Rd7, NRc7C(0)0Ra7, C(=NRe7)1\1Rc7Rd7,
NRc7C(=NRe7)
NRc3Rd7, \ Rb7,
)
S(0)1\1Rc7Rd7, S(0)2R17, NRc7S(0)2R1)7, NRc7S(0)2NRc7Rd7,
and S(0)2NRc7Rd7;
or Rcl and Rd2 together with the N atom to which they are attached form a 4-7
membered heterocycloalkyl group optionally substituted with 1, 2, or 3
substituents
independently selected from CN, halo, C1-4 alkyl, C14 haloalkyl, C1-6
haloalkyl, C2-6 alkenyl,
C2-6 alkynyl, CN, OR a7, SRa7, C(0)Rb7, C(0)NRc7Rd7, C(0)0Ra7, OC(0)Rb7,
OC(0)NRc7Rd7,
NRc7Rd7, NRc7C(0)Rb7, NRc7C(0)NRc7Rd7, NRc7C(0)0Ra7, C(=NRe7)1\1Rc7Rd7,
NRc7C(=NRe7)
NRc3Rd7, \ Rb7,
)
S(0)1\1Rc7Rd7, S(0)2R17, NRc7S(0)2R1)7, NRc7S(0)2NRc7Rd7,
and S(0)2NRc7Rd7;
or Rc2 and Rd2 together with the N atom to which they are attached form a 4-7
membered heterocycloalkyl group optionally substituted with 1, 2, or 3
substituents
independently selected from CN, halo, C14 alkyl, C1-4 haloalkyl, C1-6
haloalkyl, C2-6 alkenyl,
C2-6 alkynyl, CN, OR a7, SRa7, C(0)Rb7, C(0)NRc7Rd7, C(0)0Ra7, OC(0)Rb7,
OC(0)NRc7Rd7,
NRc7Rd7, NRc7C(0)Rb7, NRc7C(0)NRc7Rd7, NRc7C(0)0Ra7, C(=NRe7)1\1Rc7Rd7,
NRc7C(=NRe7)
NRc3Rd7, \ Rb7,
)
S(0)1\1Rc7Rd7, S(0)2Rb7, NRc7S(0)2R1)7, NRc7S(0)2NRc7Rd7,
and S(0)2NRc7Rd7;
or Rc3 and Rd3 together with the N atom to which they are attached form a 4-7
membered heterocycloalkyl group optionally substituted with 1, 2, or 3
substituents
independently selected from CN, halo, C1-4 alkyl, C1-4 haloalkyl, C1-6
haloalkyl, C2-6 alkenyl,
C2-6 alkynyl, CN, OR a7, SRa7, C(0)R'7, C(0)NRc7Rd7, C(0)0Ra7, OC(0)Rb7,
OC(0)NRc7Rd7,
NRc7Rd7, NRc7C(0)Rb7, NRc7C(0)NRc7Rd7, NRc7C(0)0Ra7, C(=NRe7)1\1Rc7Rd7,
NRc7C(=NRe7)
NRc3Rd7, \ Rb7,
)
S(0)1\1Rc7Rd7, S(0)2R17, NRc7S(0)2R1)7, NRc7S(0)2NRc7Rd7,
and S(0)2NRc7Rd7;
Ra7, Rb7, Rc7, and Rd7 are independently selected from H, C1-6 alkyl, C1-6
haloalkyl, C2-
6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered
heteroaryl, 4-10 membered
heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10
membered heteroaryl-
C1-4 alkyl, and 4-10 membered heterocycloalkyl-C14 alkyl, wherein said C1-6
alkyl, C1-6
haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10
membered heteroaryl, 4-
10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4
alkyl, 5-10
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membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl
are each
optionally substituted with 1, 2, or 3 substituents independently selected
from OH, CN,
amino, halo, C1-6 alkyl, C1-6 alkoxy, C1-6ha10a1ky1, and C1-6ha10a1k0xy;
each Re, Re', Re2, R3,
and Re' is independently selected from H, C1-4 alkyl, and CN;
a is 0 or 1;
m is 0 or 1;
n is 0 or 1;
p is 0 or 1;
q is 0 or 1;
r is 0 or 1;
wherein any aforementioned heteroaryl or heterocycloalkyl group comprises 1,
2, 3,
or 4 ring-forming heteroatoms independently selected from 0, N, and S; and
wherein one or more ring-forming C or N atoms of any aforementioned
heterocycloalkyl group is optionally substituted by 1 or 2 oxo (=0) groups.
In some embodiments, X is CF3, Br, or Cl. In some embodiments, X is CF3. In
some
embodiments, X is Br or Cl. In some embodiments, X is Br. In some embodiments,
X is Cl.
In some embodiments, Yl is NR Y or 0. In some embodiments, Yl is NR. In some
embodiments, Yl is NH. In some embodiments, Yl is 0. In some embodiments, Yl
is NH or
0.
In some embodiments, Y2 is 0, NR, or C(=0)NRY. In some embodiments, Y2 is 0,
NH, NCH3, or C(=0)NH. In some embodiments, Y2 is 0 or NR. In some embodiments,
Y2
is 0. In some embodments, Y2 is NR. In some embodiments, Y2 is 0, NH, or NCH3.
In
some embodiments, Y2 is NH or NCH3. In some embodiments, Y2 is NH. In some
embodments, Y2 is NCH3.
In some embodiments, Y3 is C(=0)NRY. In some embodiments, Y3 is C(=O)N}{. In
some embodiments, Y3 is C(=0)NCH3. In some embodiments, Y3 is C(=0)NCH2. In
some
embodiments, Y3 is C(=0)NH or C(=0)NCH3.
In some embodiments, RY of Yl is H.
In some embodiments, RY of Y2 is H or C1-4 alkyl. In some embodiments, RY of
Y2 is
H or methyl. In some embodiments, RY of Y2 is H. In some embodiments, RY of Y2
is
methyl.
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In some embodiments, RY of Y3 is H or C1-4 alkyl. In some embodiments, RY of
Y3 is
H, methyl, or ethyl. In some embodiments, RY of Y3 is H. In some embodiments,
RY of Y3 is
methyl. In some embodiments, RY of Y3 is is ethyl. In some embodiments, RY of
Y3 is CH2.
In some embodiments, Rl, R2, R3, R4, R5, R6, R7, R8, R9, Rth, R",
and R12 are each
independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2,
ORa3, SRa3,
C(0)R'3, C(0)NRc3Rd3, C(0)0Ra3, OC(0)Rb3, OC(0)NRc3Rd3, NRc3Rd3, NRc3C(0)Rb3,
NRc3C(0)0Ra3, NRc3C(0)NRc3Rd3, NRc3S(0)2R13, NRc3S(0)2NRc3Rd3, S(0)2R13, and
S(0)2NRc3Rd3; wherein said C1-6 alkyl is optionally substituted with 1, 2, 3,
4, or 5
substituents independently selected from halo, CN, NO2, ORa3, SRa3, C(0)Rb3,
C(0)NRc3Rd3,
C(0)0Ra3, OC(0)Rb3, OC(0)NRc3Rd3, NRc3Rd3, NRc3C(0)Rb3, NRc3C(0)0Ra3,
NRc3C(0)NRc3Rd3, NRc3S(0)2R1)3, NRc3S(0)2NRc3Rd3, S(0)2R'3, and S(0)2NRc3Rd3.
In some embodiments, Rl, R2, R3, R4, R5, R6, R7, R8, R9, Rth, R",
and R12 are each
independently selected from H, halo, C1-6 alkyl, and C1-6 haloalkyl, wherein
said C1-6 alkyl is
optionally substituted with 1 or 2 substituents independently selected from
halo, CN, NO2,
ORa3, C(0)Rb3, C(0)NRc3Rd3, C(0)0Ra3, NRc3Rd3, NRc3C(0)Rb3, S(0)2R13, and
S(0)2NRc3Rd3.
In some embodiments, Rl, R2, R3, R4, R5, R6, R7, R8, R9, Rth, R",
and R12 are each
independently selected from H, halo, C1-6 alkyl, and C1-6 haloalkyl, wherein
said C1-6 alkyl is
optionally substituted with ORa3.
In some embodiments, R2, R5, R6, R7, and R8 are each independently selected
from H, halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(0)R'3,
C(0)NRc3Rd3,
C(0)0Ra3, OC(0)Rb3, OC(0)NRc3Rd3, NRc3Rd3, NRc3C(0)Rb3, NRc3C(0)0Ra3,
NRc3C(0)NRc3Rd3, NRc3S(0)2R1)3, NRc3S(0)2NRc3Rd3, S(0)2R13, and S(0)2NRc3Rd3;
wherein
said C1-6 alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents
independently
selected from halo, CN, NO2, OR a3, SRa3, C(0)R'3, C(0)NRc3Rd3, C(0)0Ra3,
OC(0)Rb3,
OC(0)NRc3Rd3, NRc3Rd3, NRc3C(0)Rb3, NRc3C(0)0Ra3, NRc3C(0)NRc3Rd3,
NRc3S(0)2Rb3,
NRc3S(0)2NRc3Rd3, S(0)2R13, and S(0)2NRc3Rd3.
In some embodiments, R2, R5, R6, R7, and R8 are each independently
selected
from H, halo, C1-6 alkyl, and C1-6 haloalkyl, wherein said C1-6 alkyl is
optionally substituted
.. with 1 or 2 substituents independently selected from halo, CN, NO2, ORa3,
C(0)R'3,
C(0)NRc3Rd3, C(0)0Ra3, NRc3Rd3, NRc3C(0)Rb3, S(0)2R13, and S(0)2NRc3Rd3.
In some embodiments, R2, R5, R6, R7, and R8 are each independently
selected
from H, halo, C1-6 alkyl, and C1-6 haloalkyl, wherein said C1-6 alkyl is
optionally substituted
with ORa3.
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In some embodiments, Rl is H or C1-6 alkyl; wherein said C1-6 alkyl is
optionally
substituted with ORa3, NRc3Rd3, and NRc3C(0)Rb3. In some embodiments, Rl is H
or C1-6
alkyl; wherein said C1-6 alkyl is optionally substituted with ORa3. In some
embodiments, Rl
is H or C1-6 alkyl; wherein said C1-6 alkyl is optionally substituted with
methoxy. In some
embodiments, Rl is H or methyl; wherein said methyl is optionally substituted
with methoxy.
In some embodiments, Rl is H, methyl, methoxymethyl, CH2OH, CH(OH)CH3,
CH2NHCH2CF3 or CH2NHC(0)CH3. In some embodiments, Rl is H, methyl, or
methoxymethyl.
In some embodiments, Rl is C1-6 alkyl optionally substituted with ORa3. In
some
embodiments, Rl is C1-6 alkyl optionally substituted with methoxy. In some
embodiments, Rl
is methyl optionally substituted with methoxy. In some embodiments, Rl is
methyl. In some
embodiments, Rl is methoxymethyl.
In some embodiments, Rl is H.
In some embodiments, R2 is H.
In some embodiments, R5 is H or C1-6 alkyl.
In some embodiments, R5 is methyl.
In some embodiments, R5 is H.
In some embodiments, R6 is H.
In some embodiments, R7 is H or C1-6 alkyl.
In some embodiments, R7 is CH2.
In some embodiments, R7 is H.
In some embodiments, R8 is H.
In some embodiments, Rl and an RY group of Yl, together with the atoms to
which
they are attached and together with the atoms forming Yl form a 4-10 membered
heterocycloalkyl ring, optionally substituted with 1, 2, or 3 substituents
independently
selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl,
CN, NO2, ORa3, SRa3,
C(0)R'3, C(0)NRc3Rd3, C(0)0Ra3, OC(0)Rb3, OC(0)NRc3Rd3, NRc3Rd3, NRc3C(0)Rb3,
NRc3C(0)0Ra3, NRc3C(0)NRc3Rd3, C(=NRe3)Rb3, C(=NRe3)NRc3Rd3,
NRc3C(=NRe3)NRc3Rd3,
NRc3S(0)Rb3, NRc3S(0)2R1)3, NRc3S(0)2NR 6Rd3, S(0)R'3, S(0)NRc3Rd3, S(0)2R13,
and
S(0)2NRc3Rd3.
In some embodiments, Rl and an RY group of Yl, together with the atoms to
which
they are attached and together with the atoms forming Yl form an azetidine
ring, optionally
substituted with 1, 2, or 3 substituents independently selected from halo, C1-
6 alkyl, C2-6
alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(0)R'3,
C(0)NRc3Rd3,
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C(0)0Ra3, OC(0)Rb3, OC(0)NRc3Rd3, NRc3Rd3, NRc3C(0)Rb3, NRc3C(0)0Ra3,
NRc3C(0)NRc3Rd3, C(=NRe3)Rb3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3,
NRc3S(0)Rb3,
NRc3S(0)2R13, NRc3S(0)2NRc3Rd3, \ Rb3,
)
S(0)NRc3Rd3, S(0)2R13, and S(0)2NRc3Rd3.
In some embodiments, Rl and an RY group of Yl, together with the atoms to
which
they are attached and together with the atoms forming Yl form an azetidine
ring.
In some embodiments, R7 and an RY group of Y3, together with the atoms to
which
they are attached and together with the atoms forming Y3 and together with the
carbon atoms
substituted by R9, R10, RH, and tc -12,
if present, form a 4-10 membered heterocycloalkyl ring,
optionally substituted with 1, 2, or 3 substituents independently selected
from halo, C1-6 alkyl,
.. C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(0)Rb3,
C(0)NRc3Rd3,
C(0)0Ra3, OC(0)Rb3, OC(0)NRc3Rd3, NRc3Rd3, NRc3C(0)Rb3, NRc3C(0)0Ra3,
NRc3C(0)NRc3Rd3, C(=NRe3)Rb3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3,
NRc3S(0)Rb3,
NRc3S(0)2R13, NRc3S(0)2NRc3Rd3, \ Rb3,
)
S(0)NRc3Rd3, S(0)2R13, and S(0)2NRc3Rd3.
In some embodiments, R7 and an RY group of Y3, together with the atoms to
which
they are attached and together with the atoms forming Y3 and together with the
carbon atoms
substituted by R9, R10, RH, and lc -12,
if present, form an oxopyrrolidine ring or pyrrolidine
ring, optionally substituted with 1, 2, or 3 substituents independently
selected from halo, C1-6
alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa3, SRa3,
C(0)Rb3,
C(0)NRc3Rd3, C(0)0Ra3, OC(0)Rb3, OC(0)NRc3Rd3, NRc3Rd3, NRc3C(0)Rb3,
NRc3C(0)0Ra3, NRc3C(0)NRc3Rd3, C(=NRe3)Rb3, C(=NRe3)NRc3Rd3,
NRc3C(=NRe3)NRc3Rd3,
NRc3S(0)Rb3, NRc3S(0)2R1)3, NRc3S(0)2NR
c3Rd3, \ Rb3,
)
S(0)NRc3Rd3, S(0)2R13, and
S(0)2NRc3Rd3 .
In some embodiments, R7 and an RY group of Y3, together with the atoms to
which
they are attached and together with the atoms forming Y3 and together with the
carbon atoms
substituted by R9, R10, RH, and tc -12,
if present, form an pyrrolidine ring or oxopyrrolidine
ring.
In some embodiments, R7 and an RY group of Y3, together with the atoms to
which
they are attached and together with the atoms forming Y3 and together with the
carbon atoms
substituted by R9, R10, RH, and K-12,
if present, form an oxopyrrolidine ring.
In some embodiments, R7 and an RY group of Y3, together with the atoms to
which
they are attached and together with the atoms forming Y3 and together with the
carbon atoms
substituted by R9, R10, RH, and lc -12,
if present, form an oxopiperidine ring.
In some embodiments, Ring D is a monocyclic or polycyclic 4-10 membered
heterocycloalkyl group optionally substituted with 1, 2, or 3 groups
independently selected
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from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2,
ORa2, SRa2,
C(0)R'2, 0)NRc2-rµ d2,
C(0)0Ra2, OC(0)Rb2, OC(0)NRc2Rd2, (-NRe2)NRc2Rd2,
NRc2C(-NRe2)NRc2Rd2, NRc2Rd2, NRc2c(0)Rb2, xmc2
1N K C(0)0Ra2, NRc2C(0)NRc2Rd2,
NRc2 s (0 \ )1(b2,
NRc2S(0)2R1)2, NRc2S(0)2NRc2Rd2,)Rb2, S(0) NRc2xK d2,
S(0)2R'2, and
S(0)2NRc2Rd2, wherein the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each
optionally
substituted with 1, 2, or 3 groups independently selected from halo, CN, NO2,
OR, SRa2,
C(0)R'2, 0 K
)NRc2-r. d2,
C(0)0Ra2, OC(0)Rb2, OC(0)NRc2Rd2, (-NRe2)NRc2Rd2,
NRc2C(-NRe2)NRc2Rd2, NRc2Rd2, NRc2c(0)Rb2, 1N -r-r". C2
K C(0)0Ra2, NRc2C(0)NRc2Rd2,
NRc2 s (0 \ Rb2,
) NRc2S(0)2R1)2, NRc2S(0)2NRc2Rd2,)Rb2, S(0) NRc2K d2,
S(0)2R12, and
S(0)2NRc2Rd2.
In some embodiments, Ring D is a monocyclic or polycyclic 4-6 membered
heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents
independently
selected from halo, CN, OR, C(0)NRc2Rd2, C1-6 alkyl, and C1-6 haloalkyl.
In some embodiments, Ring D is a monocyclic or polycyclic 4-6 membered
heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents
independently
selected from halo, ORa2, C1-6 alkyl, and C1-6 haloalkyl.
In some embodiments, Ring D is 3-azabicyclo[3.1.01hexane.
In some embodiments, Ring D is a monocyclic 4-6 membered heterocycloalkyl
group
optionally substituted with 1, 2, 3, or 4 substituents independently selected
from halo, ORa2,
C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, Ring D is a polycyclic 10-
membered
heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents
independently
selected from halo, ORa2, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments,
Ring D is an
azetidine ring or piperidine ring; each of which is optionally substituted
with 1, 2, 3, or 4
substituents independently selected from halo, ORa2, C1-6 alkyl, and C1-6
haloalkyl. In some
embodiments, Ring D is a piperidine ring optionally substituted with 1, 2, 3,
or 4 substituents
independently selected from halo, ORa2, C1-6 alkyl, and C1-6 haloalkyl. In
some embodiments,
Ring D is a piperidine ring optionally substituted with 1 or 2 subsitutents
independently
selected from OH, F, C(0)NH2, or CN. In some embodiments, Ring D is an
azetidine ring
optionally substituted with 1, 2, 3, or 4 substituents independently selected
from halo, ORa2,
C1-6 alkyl, and C1-6 haloalkyl.
In some embodiments, Ring D is a monocyclic 4-6 membered heterocycloalkyl
group.
In some embodiments, Ring D is a polycyclic 10-membered heterocycloalkyl
group. In some
embodiments, Ring D is an azetidine ring or piperidine ring. In some
embodiments, Ring D is
a piperidine ring. In some embodiments, Ring D is an azetidine ring.
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In some embodiments, Ring D is a monocyclic 4-6 membered heterocycloalkyl
group
optionally substituted with 1, 2, 3, or 4 substituents independently selected
from halo, ORa2,
C1-6 alkyl, and C1-6 haloalkyl.
In some embodiments, Ring D is an azetidine ring or piperidine ring optionally
substituted with ORa2.
In some embodiments, Ring D is a piperidine ring optionally substituted with
OH.
In some embodiments, Ring D is a piperidine ring.
In some embodiments, Z is Cyz, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,
C1-6
haloalkyl, CN, NO2, ORE', SR', C(0)R', C(0)NWRd, C(0)0Ra, OC(0)Rb, OC(0)NWRd,
NWRd, NWC(0)Rb, NWC(0)0Ra, NWC(0)NWRd, C(=NRe)Rb, C(=NRe)NWRd,
NWC(=NRe)NWRd, NWS(0)Rb, NWS(0)2R1), NWS(0)2NWRd, S(0)R', S(0)NWRd,
S(0)2R1, and S(0)2NRcRd; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,
and C1-6
haloalkyl of Z are each optionally substituted with 1, 2, 3, 4, or 5
substituents independently
selected from Cyz, halo, CN, NO2, OW, SR', C(0)R', C(0)NWRd, C(0)0Ra, OC(0)Rb,
OC(0)NWRd, C(=NRe)NWRd, NWC(=NRe)NWRd, NWRd, NWC(0)Rb, NWC(0)0Ra,
NWC(0)NWRd, NWS(0)Rb, NWS(0)2R1), NWS(0)2NWRd, S(0)Rb, S(0)NWRd, S(0)2R1,
and S(0)2NWRd.
In some embodiments, Z is Cyz, halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2,
ORE', SR',
C(0)R', C(0)NWRd, C(0)0Ra, OC(0)Rb, OC(0)NWRd, NWRd, NWC(0)Rb, NWC(0)0Ra,
NWC(0)NWRd, NWS(0)2R1), NWS(0)2NReRd, S(0)2R1, and S(0)2NWRd; wherein said C1-
6
alkyl of Z is optionally substituted with 1, 2, 3, 4, or 5 substituents
independently selected
from Cyz, halo, CN, NO2, OW, SW, C(0)R', C(0)NWRd, C(0)0Ra, OC(0)Rb,
OC(0)NWRd, NWRd, NWC(0)Rb, NWC(0)0Ra, NWC(0)NWRd, NWS(0)2R1),
NWS(0)2NWRd, S(0)2R1, and S(0)2NWRd.
In some embodiments, Z is Cyz, halo, C1-6 alkyl, C1-6 haloalkyl, or CN.
In some embodiments, Z is Cyz.
In some embodiments, Cyz is a 5-6 membered heteroaryl group optionally
substituted
by 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-
6 alkenyl, C2-6
alkynyl, C1-6 haloalkyl, CN, NO2, ORai, sRai, c(coRbi,
) C(0)
C(0)0Ral, OC(0)Rbl,
OC(0)NRc1Rdl, c(-NRei)NRciRdi, NRcic(-NRei)NRciRdi, NRciRdi, NRcicocoRbi,
NRcic(0)0Rai, NRcic(0)NRciRdi, NRcis(0)Rbi, 'VIC xmci
S(0)2Rbi, NRciS(0)2NRciRdl,
l
S(0)R', S(0)NRcl-r-+ dl,
S(0)2R, and S(0)2NRciRdl, wherein the alkyl, C2-6 alkenyl, and C2-6
alkynyl are optionally substituted with 1, 2, or 3 substituents independently
selected from
halo, CN, NO2, ORal, SRal, C(0)R', C(0)NR-',
C(0)0Ral, OC(0)Rbi, OC(0)NWiRdi,
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c(-NRel)NRc1Rdl, NRc1c(-NRel)NRc1Rdl, NRc1Rdl, NRcicocoRbl, cl
1NK C(0)0Ral,
NRc1C(0)NRc1Rdl, NRcls(0)Rbl, 'VX TTNIC Cl
S(0) 2Rbl, x-riN_K-r,c1S(0)2NRc1Rdl, s(o)nbl,
S(0)NRciRdl,
S(0)2R, and S(0)2NRclRdl.
In some embodiments, Cyz is a 5 or 6-membered heteroaryl group substituted
with
halo, CN, methyl, or C1-3 haloalkyl.
In some embodiments, Cyz is a 5 membered heteroaryl group substituted with
halo,
CN or C1-3 haloalkyl. In some embodiments, Cyz is a a 6-membered heteroaryl
group
substituted with halo, CN, methyl, or C1-3 haloalkyl. In some embodiments, Cyz
is a 6
membered heteroaryl group substituted with halo, CN or C1-3 haloalkyl.
In some embodiments, Cyz is a pyrimidinyl, pyrazinyl, pyridinyl, or thiazolyl
group
substituted with halo, CN or C1-3 haloalkyl. In some embodiments, Cyz is a
pyrimidinyl,
pyrazinyl, or pyridinyl group substituted with halo, CN or C1-3 haloalkyl. In
some
embodiments, Cyz is a pyrimidinyl or pyrazinyl group substituted with halo, CN
or C1-3
haloalkyl. In some embodiments, Cyz is pyrimidinyl substituted with CF3. In
some
embodiments, Cyz is a thiazolyl group substituted with halo, CN or C1-3
haloalkyl.
In some embodiments, Cyz is selected from 5-(trifluoromethyl)pyrimidin-2-yl, 5-
(trifluoromethypthiazol-2-yl, 5-(trifluoromethyl)pyrazin-2-yl, 5-
(difluoromethyl)pyrimidin-2-
yl, 5-(difluoromethyl)pyrazin-2-yl, 5-floropyrimidin-2-yl, 5-chloropyrimidin-2-
yl, 5-
chloropyrazin-2-yl, 5-bromopyrimidin-2-yl, 5-cyanopyridin-2-yl, 5-cyanothiazol-
2-yl, 5-
cyanopyrazin-2-yl, 5-methylpyrimidin-2-yl.
In some embodiments, Cyz is selected from 5-(trifluoromethyl)pyrimidin-2-yl, 5-
(trifluoromethypthiazol-2-yl, 5-(trifluoromethyppyrazin-2-yl, 5-cyanopyridin-2-
yl, 5-
(difluoromethyl)pyrimidin-2-yl, 5-chloropyrimidin-2-yl, 5-
(difluoromethyl)pyrazin-2-yl, and
5-bromopyrimidin-2-yl.
In some embodiments, Cyz is 5-(trifluoromethyl)pyrimidin-2-yl.
In some embodiments, m is 1.
In some embodiments, n is 0.
In some embodiments, p is 0.
In some embodiments, q is 0.
In some embodiments, r is 1. In some embodiments, r is 0.
In some embodiments, a is 0.
In some embodiments, X is CF3, Yl is NR, Y2 is 0, Y3 is C(0)NR, RI- is methyl,
R2 is H, R5 is H, R6 is H, R7 is CH2, R8 is H, Ring D is piperidine
substituted with OH, and Z
is Cyz wherein Cyz is pyrimidinyl substituted with CF3.
16
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In some embodiments, provided herein is a compound having Formula ha:
0
HN R1R2
3-I-- 0 N-Z
N
y 1
R5 R6 R7 R8
Ha,
or a pharmaceutically acceptable salt thereof
In some embodiments, provided herein is a compound having Formula IIb:
0
HN R1R2
Ly2y3 ( N-Z
N
y 1
R5 R6 R7 R8
IIb,
or a pharmaceutically acceptable salt thereof
In some embodiments, provided herein is a compound having Formula IIc:
0
HN R1R2 z1
( Z2) __ Rz
N
y 1
R5 R6 R7 R8
IIc;
or a pharmaceutically acceptable salt thereof, wherein Z1 and Z2 are each
independently
selected from N and CH, and wherein Rz is halo, CN or C1-3 haloalkyl. In some
embodiments, Rz is selected from CF3, CN, CF2H, and Cl.
In some embodiments, the compound of the invention has Formula IId:
17
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0
X j-(
NH
0 Z
yL
R2 y
R5 R6 __________________________________
lid;
or a pharmaceutically acceptable salt thereof
In some embodiments, the compound of the invention has Formula Ile:
0
X j=
NH
I
- 0
R1
IR(Y (N'C)
R5 R6
lie;
or a pharmaceutically acceptable salt thereof
In some embodiments, provided herein is a compound of Formula I, or a
pharmaceutically acceptable salt thereof, wherein:
X is Cl, Br, or CF3;
A is a group having a formula that is (A-1a):
R1R2
y3 __________________________________ D N-Z
j
R5 R6 R7 R8 (A-1a)
yl, and Y3 are each independently selected from 0, NR, C(=0), and C(0)NR,
wherein each RY is independently H or C1-4 alkyl;
Z is Cyz;
Cyz is selected from 5-10 membered heteroaryl optionally substituted by 1, 2,
3, or 4
substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6
alkynyl, C1-6
haloalkyl, CN, NO2, ORal, SRal, C(0) R', C(0)NRci¨ d 1,
C(0)0Ra 1 , OC(0)Rbl,
0C(0)NRc1Rdl, c(¨NRel)NRc1Rdl, NRc1c(¨NRel)NRc1Rdl, NRc1Rdl, NRcicocoRbl,
NRc1c (0)0Ral, NRc1C(0)NRc1Rdl, NRclsocoRbl, INK r-r=c tcl S(0)2TN bl,
NRc1S(0)2NRciRdl,
() 0
s(cr-NIC bl, S )NRcl-rNdl,
S(0)2R, and S(0)2NRciRdl, wherein the alkyl, C2-6 alkenyl, and C2-6
alkynyl are optionally substituted with 1, 2, or 3 substituents independently
selected from
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halo, CN, NO2, ORal, sRal, coRbl, C(0)NReiRdi, C(0)0Ral, OC(0)Rbi,
OC(0)NReiRdi,
c(-NRel)NRc1Rdl, NRcic(-NRel)NRc1Rdl, NRc1Rdl, NRc1c(0)Rbl, IC 'Vxmcl
C(0)0Ral,
NRe1C(0)NRc1Rdl, NRcls(0)Rbl, 'VIC XMC1
S(0)2Rbi, NRelS(0)2NRc1Rdl, s(ombl,
S(0)NRe'Rdl,
S(0)2R', and S(0)2NRciRd1;
Ring D is a monocyclic or polycyclic 4-10 membered heterocycloalkyl group
optionally substituted with 1, 2, or 3 groups independently selected from
halo, C1-6 alkyl, C2-6
alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa2, SR, C(0)R'2,
C(0)NRe2Rd2,
C(0)OR, OC(0)Rb2, OC(0)NRc2Rd2, (-NRe2)NRc2Rd2, NRc2c(_ NRe2)NRc2Rd2, NRc2Rd2,
NRe2C(0)Rb2, NRe2C(0)0Ra2, NRe2C(0)NRc2Rd2, NRc2s(0)Rb2, x C2
IN IC S10/2Rb2,
NRC2S(0)2NRC2Rd2, S(0)R'2,
S(0 )N1RC2Rd2, S10/2R12, and S(0)2NRc2Rd2, wherein the C1-6
alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1,
2, or 3 groups
independently selected from halo, CN, NO2, OR a2, SRa2, C(0)R'2, C(0)NRe2Rd2,
C(0)OR,
OC(0)Rb2, OC(0)NRc2Rd2, (-NRe2)NRc2Rd2, NRc2c NRe2)NRc2Rd2, NRc2Rd2,
NRe2C(0)Rb2, NRe2C(0)0Ra2, NRe2C(0)NRc2Rd2, NRc2socoRb2, c
AK2 S(0)2Rb2,
NRc2S(0)2NRc2Rd2, S(0)R'2,
S(0)NRc2Rd2, S(0)2R12, and S(0)2NRc2Rd2;
R2, R5, R6, R7, and R8 are each independently selected from H, halo, C1-6
alkyl, C2-
6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10
membered heteroaryl,
4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4
alkyl, 5-10
membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN,
NO2, ORa3,
SRa3, C(0)Rb3, C(0)NRe3Rd3, C(0)0W'3, OC(0)Rb3, OC(0)NRe3Rd3, NRe3Rd3,
NRe3C(0)Rb3,
NRe3C(0)0Ra3, NRe3C(0)NRe3Rd3, C(=NRe3)Rb3, C(=NRe3)NRe3Rd3,
NRe3C(=NRe3)NRe3Rd3,
NRe3S(0)Rb3, NRe3S(0)2R1)3, NRe3S(0)2NRe3Rd3, S(0)R'3, S(0)NRe3Rd3, S(0)2R13,
and
S(0)2NRc3Rd3; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6
haloalkyl, C6-10 aryl,
C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-
10 aryl-C1-4
alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-
10 membered
heterocycloalkyl-C1-4 alkyl of said R2, R5, R6, R7, and R8 are each
optionally substituted
with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6
alkyl, C2-6 alkenyl,
6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(0)R'3, C(0)NRe3Rd3,
C(0)0Ra3,
OC(0)Rb3, OC(0)NRe3Rd3, NRe3Rd3, NRe3C(0)Rb3, NRe3C(0)0Ra3, NRe3C(0)NRe3Rd3,
C(=NRe3)Rb3, C(=NRe3)NRe3Rd3, NRe3C(=NRe3)NRe3Rd3, NRe3S(0)Rb3, NRe3S(0)2R13,
NRe3S(0)2NRe3Rd3, S(0)R'3, S(0)NRe3Rd3, S(0)2Rb3, and S(0)2NRc3Rd3;
or Rl and an RY group of Yl, together with the atoms to which they are
attached and
together with the atoms forming Yl form a 4-10 membered heterocycloalkyl ring,
optionally
substituted with 1, 2, or 3 substituents independently selected from halo, C1-
6 alkyl, C2-6
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alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(0)Rb3,
C(0)NRe3Rd3,
C(0)0Rd3, OC(0)Rb3, OC(0)NRe3Rd3, NRe3Rd3, NRe3C(0)Rb3, NRe3C(0)0Rd3,
NRe3C(0)NRe3Rd3, C(=NRe3)Rb3, C(=NRe3)NRe3Rd3, NRe3C(=NRe3)NRe3Rd3,
NRe3S(0)Rb3,
NRe3S(0)2Rb3, NRe3S(0)2NRe3Rd3, S(0)Rb3, S(0)NRc3Rd3, S(0)2R'3, and
S(0)2NRe3Rd3;
or R7 and an RY group of Y3, together with the atoms to which they are
attached and
together with the atoms forming Y3 form a 4-10 membered heterocycloalkyl ring,
optionally
substituted with 1, 2, or 3 substituents independently selected from halo, C1-
6 alkyl, C2-6
alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORd3, SRa3, C(0)Rb3,
C(0)NRe3Rd3,
C(0)0Rd3, OC(0)Rb3, OC(0)NRe3Rd3, NRe3Rd3, NRe3C(0)Rb3, NRe3C(0)0Rd3,
NRe3C(0)NRe3Rd3, C(=NRe3)Rb3, C(=NRe3)NRe3Rd3, NRe3C(=NRe3)NRe3Rd3,
NRe3S(0)Rb3,
NRe3S(0)2Rb3, NRe3S(0)2NRe3Rd3, S(0)Rb3, S(0)NRc3Rd3, S(0)2R'3, and
S(0)2NRe3Rd3;
each Re', Rb, RC, Rd, Ral, Rbl, wl, Rdl, Ra2, Rb2, Rc2, Rd2, w3, Rb3, Rc3, and
Rd3 is
independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6
alkynyl, C640 aryl,
C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-
10 aryl-C1-4
.. alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and
4-10 membered
heterocycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6
alkynyl, C640 aryl, C3-7
cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10
aryl-C1-4 alkyl,
C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10
membered
heterocycloalkyl-C1-4 alkyl of said Ra, Rb, RC, Rd, Ral, Rbl, Rcl, Rdl, Ra2,
Rb2, Rc2, Rd2, Ra3,
Rb3, Re3, and Rd3 is optionally substituted with 1, 2, or 3 substituents
independently selected
from halo, C14 alkyl, C14 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, ORd7,
SRa7, C(0)R'7,
C(0)NRe7Rd7, C(0)0Rd7, OC(0)Rb7, OC(0)NRe7Rd7, NRe7Rd7, NRe7C(0)Rb7,
NRe7C(0)NRe7Rd7, NRe7C(0)0Ra7, C(=NRe7)NRe7Rd7, NRe7C(=NRe7)NRe3Rd7, S(0)R'7,
S(0)NRe7Rd7, S(0)2R17, NRe7S(0)2R1)7, NRe7S(0)2NRe7Rd7, and S(0)2NRe7Rd7;
Ra7, Rb7, Re7, and Rd7 are independently selected from H, C1-6 alkyl, C1-6
haloalkyl, C2-
6 alkenyl, C2-6 alkynyl, C640 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl,
4-10 membered
heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10
membered heteroaryl-
C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl, wherein said C1-6
alkyl, C1-6
haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10
membered heteroaryl, 4-
.. 10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4
alkyl, 5-10
membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl
are each
optionally substituted with 1, 2, or 3 substituents independently selected
from OH, CN,
amino, halo, C1-6 alkyl, C1-6 alkoxy, C1-6ha10a1ky1, and C1-6ha10a1k0xy; and
each Re, Re', Re2, e3
tc, and Re7 is independently selected from H, C1-4 alkyl, and CN;
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wherein any aforementioned heteroaryl or heterocycloalkyl group comprises 1,
2, 3,
or 4 ring-forming heteroatoms independently selected from 0, N, and S; and
wherein one or more ring-forming C or N atoms of any aforementioned
heterocycloalkyl group is optionally substituted by 1 or 2 oxo (=0) groups.
In some embodiments, provided herein is a compound selected from:
(S)-2-(2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-ylamino)propoxy)-N-
(1-
(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide;
(S)-N-methy1-2-(2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-
ylamino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-y1)piperidin-4-
y1)acetamide;
(S)-N-methy1-2-(2-46-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-
y1)amino)propoxy)-N-(1-(5-(trifluoromethypthiazol-2-yOpiperidin-4-yOacetamide;
(S)-N-methy1-2-(2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-
ylamino)propoxy)-N-(1-(5-(trifluoromethyl)pyrazin-2-y1)piperidin-4-
y1)acetamide;
((S)-N-methy1-2-(2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-
ylamino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azetidin-3-
yl)acetamide;
(S)-N-(1-(5-cyanopyridin-2-yl)piperidin-4-y1)-N-methy1-2-(2-((6-oxo-5-
(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)acetamide;
(S)-N-ethy1-2-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-
y1)amino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-y1)piperidin-4-
y1)acetamide;
(S)-N-methy1-2-((1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-
y1)azetidin-2-
y1)methoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-y1)piperidin-4-y1)acetamide;
(S)-2-(3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-
yl)amino)propoxy)-N-methyl-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-
yl)acetamide;
5-((S)-1 -((S)-1 -(1-(5-(trifluoromethy Opy rimi din-2-y Opip eri din-4-y 0-2-
oxopy rroli din-
3-yloxy)propan-2-ylamino)-4-(trifluoromethyl)pyridazin-3(21-1)-one;
5-((S)-1 - ((R) - 1 - (1 -(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-y1)-2-
oxopyrrolidin-
3-yloxy)propan-2-ylamino)-4-(trifluoromethyl)pyridazin-3(21-1)-one;
4-chloro-5-((S)-1-(2-oxo-1-(1-(5-(trifluoromethyppyrimidin-2-yOpiperidin-4-
yOpyrrolidin-3-yloxy)propan-2-ylamino)pyridazin-3(2H)-one;
4-bromo-5-(((2S)-1-((2-oxo-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-
yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)pyridazin-3(2H)-one;
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5-4(S)-1-4(S)-2-oxo-1-(1-(5-(trifluoromethyppyrazin-2-yOpiperidin-4-
yOpyrrolidin-
3-y Doxy)prop an-2-y Damino)-4-(trifluoromethy Opy ridazin-3(2H)-one;
5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-
yl)pyrrolidin-
3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one;
6-(4-((R)-2-oxo-3 -((S)-2-((6-oxo-5 -(trifluoromethyl)-1,6-dihy dropy ridazin-
4-
yl)amino)prop oxy)pyrrolidin-l-yl)pip eridin-l-y 1)nicotinonitrile;
6-(4-((S)-2-oxo-3-((S)-2-((6-oxo-5 -(trifluoromethyl)-1,6-dihy dropyridazin-4-
yl)amino)prop oxy)py rrolidin-l-yl)pip eridin-l-y 1)nicotinonitrile;
5-(((S)-1-(((S)-1-(1-(5-(difluoromethyl)pyrimidin-2-yl)piperidin-4-y1)-2-
oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-
one;
5-(((S)-1-(((R)-1-(1-(5-(difluoromethyl)pyrimidin-2-yl)piperidin-4-y1)-2-
oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-
one;
5-4(S)-1-4(R)-1-(1-(5-chloropyrimidin-2-yOpiperidin-4-y1)-2-oxopyrrolidin-3-
y0oxy)propan-2-y0amino)-4-(trifluoromethyl)pyridazin-3(2H)-one;
6-(4-((S)-3-((S)-3 -methoxy -2-((6-oxo-5 -(trifluoromethyl)-1,6-dihy
dropyridazin-4-
yl)amino)propoxy)-2-oxopy rrolidin-l-yl)piperidin-l-yl)nicotinonitrile;
6-(4-((R)-3-((S)-3-methoxy -2-((6-oxo-5 -(trifluoromethyl)-1,6-dihy dropy
ridazin-4-
yl)amino)propoxy)-2-oxopy rrolidin-l-yl)piperidin-l-yl)nicotinonitrile;
5-(((S)-1-methoxy-3 -(((S)-2-oxo-1-(1-(5-(trifluoromethy Opy razin-2-y Opip
eridin-4-
yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-
one;
(S)-N-methyl-2-(2-(6-oxo-5 -(trifluoromethyl)-1,6-dihy dropyridazin-4-
ylamino)prop oxy)-N-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-
yl)acetamide;
5-(((S)-1-methoxy-3-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-
yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-
one;
5-(((S)-1-methoxy-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-
yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-
one;
5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyppyrimidin-2-yOpiperidin-4-
yOpyrrolidin-3-y0oxy)propan-2-y0oxy)-4-(trifluoromethyppyridazin-3(2H)-one;
5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)py rimidin-2-yl)pip eridin-4-
yOpyrrolidin-3-y0oxy)propan-2-y0oxy)-4-(trifluoromethyppyridazin-3(2H)-one;
4-(trifluoromethyl)-5-(((2S)-1-((1-(1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-
yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)pyridazin-3(2H)-one;
5-(((S)-1-(((S)-1-(1-(5-(difluoromethyl)pyrazin-2-yl)piperidin-4-y1)-2-
oxopyrrolidin-
3 -yl)oxy)prop an-2-yl)amino)-4-(trifluoromethyl)py ridazin-3(2H)-one;
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5-(((S)-1-(((R)-1-(1-(5-(difluoromethyl)pyrazin-2-yl)piperidin-4-y1)-2-
oxopyrrolidin-
3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one;
4-bromo-5-4(S)-1-4(S)-2-oxo-1-(1-(5-(trifluoromethyppyrimidin-2-yOpiperidin-4-
yOpyrrolidin-3-y0oxy)propan-2-y0oxy)pyridazin-3(2H)-one;
5-4(S)-1-4(R)-1-(1-(5-bromopyrimidin-2-yOpiperidin-4-y1)-2-oxopyrrolidin-3-
y0oxy)propan-2-y0amino)-4-(trifluoromethyl)pyridazin-3(2H)-one;
(S)-N-methy1-2-(2-46-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-
y1)oxy)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-y1)piperidin-4-
y1)acetamide;
5-(((S)-1-(((S)-2-oxo-1-(1-(5 -(trifluoromethyl)pyrimidin-2-yl)piperidin-4-
yl)pyrrolidin-3-yl)amino)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-
one;
5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-
yl)pyrrolidin-3-yl)amino)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-
one;
5-(((R)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-
yl)pyrrolidin-3-yl)amino)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-
one;
5-(((R)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-
yl)pyrrolidin-3-yl)amino)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-
one;
5-(((2S)-1-((1-(1-(5-(difluoromethyl)pyrimidin-2-yl)piperidin-4-y1)-2-
oxopyrrolidin-
3 -yl)oxy)prop an-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one;
(S)-2-(2-((5-bromo-6-oxo-1,6-dihy dropy ridazin-4-yl)oxy)propoxy)-N-methyl-N-
(1-
(5 -(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide;
5-(((2S)-1-(methyl(2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-
yl)pyrrolidin-3-yl)amino)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-
one;
6-(4-(2-oxo-3-((S)-2-((6-oxo-5 -(trifluoromethyl)-1,6-dihy dropy ridazin-4-
yl)oxy)prop oxy)pyrrolidin-l-yl)pip eridin-l-yl)nicotinonitril e;
5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-
yl)pyrrolidin-
3 -yl)oxy)prop an-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one;
5-(((S)-1-(((R)-2-oxo-1-(1-(5 -(trifluoromethyl)py razin-2-yl)piperidin-4-
yl)pyrrolidin-
3 -yl)oxy)prop an-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one;
4-bromo-5 -(((S)-1-(((R)-2-oxo-1-(1-(5 -(trifluoromethy Opy rimidin-2-y Opip
eridin-4-
yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)pyridazin-3(2H)-one;
N-((3R,4R)-3-hy droxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-y1)-2-
((S)-2-
((6-oxo-5 -(trifluoromethyl)-1,6-dihy dropy ridazin-4-yl)amino)prop
oxy)acetamide; and
N-43S,4S)-3-hydroxy-1-(5-(trifluoromethyppyrimidin-2-yOpiperidin-4-y1)-2-((S)-
2-
46-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-y1)amino)propoxy)acetamide;
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or a pharmaceutically acceptable salt of any of the aforementioned.
In some embodiments, provided herein is a compound selected from:
(S)-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-
yl)amino)propoCyxy)-1'-(5-(trifluoromethyppyrimidin-2-y1)41,4'-bipiperidin1-2-
one;
(R)-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-
y0amino)propoxy)-
11-(5-(trifluoromethyl)pyrimidin-2-y1)41,4'-bipiperidin1-2-one;
5-(((S)-1-(((S)-4,4-dimethy1-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-
4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-
one;
5-(((S)-1-(((R)-4,4-dimethy1-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-
4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-
one;
(R)-6-(4-(2-oxo-3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihy dropyridazin-4-
yl)amino)ethoxy)pyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile;
(S)-6-(4-(2-oxo-3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihy dropyridazin-4-
yl)amino)ethoxy)pyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile;
5-(((S)-1-(((3S,4R)-4-methy1-2-oxo-1-(1-(5-(trifluoromethyppyrimidin-2-
yOpiperidin-4-yOpyrrolidin-3-y0oxy)propan-2-y0amino)-4-
(trifluoromethyl)pyridazin-
3(2H)-one;
5-(((S)- 1 -(((3R,4 S)-4-methy1-2-oxo- 1-( 1 -(5 -(trifluoromethyl)py rimi din-
2-
yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-
(trifluoromethyl)pyridazin-
3(2H)-one;
5-4(S)-1-4(R)-1-43R,4R)-3-fluoro-1-(5-(trifluoromethyppyrimidin-2-yOpiperidin-
4-
y1)-2-oxopyrrolidin-3-y0oxy)propan-2-y0amino)-4-(trifluoromethyl)pyridazin-
3(2H)-one;
5-(((S)-1 -(((R)- 1-((3 S,4S )-3 -fluoro- 1 -(5 -(trifluoromethy Opy
y1)-2-oxopyrrolidin-3-y0oxy)propan-2-y0amino)-4-(trifluoromethyl)pyridazin-
3(2H)-one;
5-(((S)-1 -(((R)- 1-((3 S,4R)-3 -fluoro-1 -(5 -(trifluoromethyppyrimidin-2-
yOpiperidin-4-
y1)-2-oxopyrrolidin-3-y0oxy)propan-2-y0amino)-4-(trifluoromethyl)pyridazin-
3(2H)-one;
5-4(S)-1-4(R)-1-43R,4S)-3-fluoro-1-(5-(trifluoromethyppyrimidin-2-yOpiperidin-
4-
y1)-2-oxopyrrolidin-3-y0oxy)propan-2-y0amino)-4-(trifluoromethyl)pyridazin-
3(2H)-one;
6-((R)-3,3-difluoro-4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-
dihydropyridazin-4-yl)amino)propoxy)pyrrolidin-1-y1)piperidin-1-
y1)nicotinonitrile;
6-((S)-3,3-difluoro-4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-
dihydropyridazin-4-yl)amino)propoxy)pyrrolidin-1-y1)piperidin-1-
y1)nicotinonitrile;
5-(((S)-1-(((R)-1-(1-(5-chloropyrazin-2-yOpiperidin-4-y1)-2-oxopyrrolidin-3-
y0oxy)propan-2-y0amino)-4-(trifluoromethyl)pyridazin-3(2H)-one;
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5-4(S)-1-4(R)-1-(1-(5-fluoropyrimidin-2-yOpiperidin-4-y1)-2-oxopyrrolidin-3-
y0oxy)propan-2-y0amino)-4-(trifluoromethyl)pyridazin-3(2H)-one;
5-(((S)-1-(((R)-2-oxo-1-((1R,5 S,6s)-3-(5-(trifluoromethyl)pyrimidin-2-y1)-3-
azabicyclo [3.1. 0] hexan-6-yOpyrrolidin-3-y0oxy)propan-2-y0amino)-4-
(trifluoromethy Opy ridazin-3 (2H)-one;
5-4(S)-1-4(R)-1-(1-(5-methylpyrimidin-2-yOpiperidin-4-y1)-2-oxopyrrolidin-3-
y0oxy)propan-2-y0amino)-4-(trifluoromethyl)pyridazin-3(2H)-one;
5-(4-((R)-2-oxo-3 -((S)-2-46-oxo-5 -(trifluoromethyl)-1,6-dihy dropy ridazin-4-
yOamino)prop oxy)pyrrolidin- 1 -yl)pip eridin- 1 -y 1)py razine-2-
carbonitrile;
4-bromo-5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-
4-
yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)pyridazin-3(2H)-one;
4-bromo-5 -(((S)-1 -(((R)-2-oxo- 1 -(1 -(5 -(trifluoromethyl)pyrazin-2-
yl)piperidin-4-
yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)pyridazin-3(2H)-one;
4-chloro-5-(((S)-1 -(((S)-2-oxo- 1 -(1 -(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-
yl)py rrolidin-3-yl)oxy)prop an-2-yl)oxy)pyridazin-3 (2H)-one;
4-chloro-5-(((S)-1 -(((R)-2-oxo- 1 -(1 -(5-(trifluoromethyl)py rimidin-2-
yl)piperidin-4-
yl)py rrolidin-3-yl)oxy)prop an-2-yl)oxy)pyridazin-3 (2H)-one;
6-(4-((R)-3-((S)-2-((5 -bromo-6-oxo-1,6-dihy dropy ridazin-4-yl)oxy)propoxy)-2-
oxopy rrolidin- 1 -yl)pip eridin- 1 -y 1)ni cotinonitrile;
6-(4-((S)-3-((S)-2-((5 -bromo-6-oxo- 1,6-dihy dropy ridazin-4-yl)oxy)propoxy)-
2-
oxopy rrolidin- 1 -yl)pip eridin- 1 -y 1)ni cotinonitrile;
5-(((S)-1-(((S)-1-(1-(5-methylpyrimidin-2-yl)piperidin-4-y1)-2-oxopyrrolidin-3-
yl)oxy)propan-2-y0oxy)-4-(trifluoromethy Opyridazin-3 (2H)-one;
5-4(S)-1-4(R)-1-(1-(5-methylpyrimidin-2-yOpiperidin-4-y1)-2-oxopyrrolidin-3-
y0oxy)propan-2-y0oxy)-4-(trifluoromethyppyridazin-3(2H)-one;
6-(4-((S)-3-((S)-3 -methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-
4-
yl)oxy)propoxy)-2-oxopyrrolidin-1 -yl)piperidin- 1 -yl)nicotinonitrile;
6-(4-((R)-3-((S)-3-methoxy-2-((6-oxo-5 -(trifluoromethyl)-1,6-dihydropyridazin-
4-
yl)oxy)propoxy)-2-oxopyrrolidin-1 -yl)piperidin- 1 -yl)nicotinonitrile;
5-(((S)-1 -methoxy-3-(((S)-2-oxo- 1 -(1 -(5-(trifluoromethy Opy rimidin-2-y
Opiperidin-4-
y Opy Doxy)prop an-2-y0oxy)-4-(trifluoromethy Opyridazin-3 (2H)-one;
5-(((S)- 1 -methoxy-3 -(((R)-2-oxo-1 -(1 -(5 -(trifluoromethyppyrimidin-2-
yOpiperidin-4-
yOpyrrolidin-3-y0oxy)propan-2-y0oxy)-4-(trifluoromethyppyridazin-3(2H)-one;
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5-4(S)-1-methoxy-3-4(S)-1-(1-(5-methylpyrimidin-2-yOpiperidin-4-y1)-2-
oxopyrrolidin-3-y0oxy)propan-2-y0oxy)-4-(trifluoromethyppyridazin-3(2H)-one;
5-(((S)- 1 -methoxy-3-(((R)- 1 -(1 -(5-methylpyrimi din-2-yl)piperidin-4-y1)-2-
oxopy rrolidin-3-yl)oxy)prop an-2-yl)oxy)-4-(trifluoromethyl)py ridazin-3 (2H)-
one;
5-(((S)- 1 -methoxy-3-(((R)- 1 -(1 -(5-methylpyrimi din-2-yl)piperidin-4-y1)-2-
oxopy rrolidin-3-yl)oxy)prop an-2-yl)amino)-4-(trifluoromethyl)pyridazin-3
(2H)-one;
2-(4-((R)-3-((S)-3-methoxy-2-((6-oxo-5 -(trifluoromethyl)- 1,6-dihy dropy
ridazin-4-
yl)amino)prop oxy)-2-oxopy rrolidin-1 -yl)piperidin- 1 -y 1)thiazole-5 -
carbonitrile;
6-(4-((S)-3-((S)-2-((5 -bromo-6-oxo- 1,6-dihy dropy ridazin-4-yl)oxy)-3-
methoxy propoxy)-2-oxopy rrolidin-1 -yl)piperidin- 1 -yl)nicotinonitril e;
6-(4-((R)-3-((S)-2-((5 -bromo-6-oxo-1,6-dihy dropy ridazin-4-yl)oxy)-3-
methoxy propoxy)-2-oxopy rrolidin-1 -yl)piperidin- 1 -yl)nicotinonitril e;
4-Bromo-5-(((S)- 1 -methoxy -3 -(((S)-2-oxo- 1 -(1 -(5 -
(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)pyridazin-3(2H)-one;
4-Bromo-5-(((S)- 1 -methoxy -3 -(((R)-2-oxo- 1 -(1 -(5-(trifluoromethyl)py
rimidin-2-
yl)piperidin-4-yl)pyrrolidin-3 -yl)oxy)propan-2-yl)oxy)pyridazin-3 (2H)-one;
5-(((S)-1 -(((R)- 1 -((3R,4R)-3 -hy droxy -1 -(5 -(trifluoromethyl)pyrimidin-2-
yl)piperidin-
4-y1)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-
3(2H)-one;
5-(((S)-1-(((R)-1-((3S,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-
4-y1)-2-oxopyrrolidin-3-y0oxy)propan-2-y0amino)-4-(trifluoromethyl)pyridazin-
3(2H)-one;
5-(((S)-1 -(((R)- 1-((3 S ,4R)-3 -hy droxy -1 -(5-(trifluoromethyl)py rimidin-
2-yl)pip eridin-
4-y1)-2-oxopyrrolidin-3 -y0oxy)propan-2-y0amino)-4-(trifluoromethyl)pyridazin-
3(2H)-one;
5-(((S)-1 -(((R)-1 -((3R,4S)-3-hy droxy -1 -(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-
4-y1)-2-oxopyrrolidin-3 -y0oxy)propan-2-y0amino)-4-(trifluoromethyl)pyridazin-
3(2H)-one;
(S)-N-((R)-2-oxo- 1 -(1 -(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-
yl)pyrrolidin-3-
y1)-2-((6-oxo-5 -(trifluoromethyl)-1,6-dihydropyridazin-4-y0amino)propanamide;
5-(((S)- 1 -(((R)-2-oxo-1 -(1 -(5-(trifluoromethyl)py rimidin-2-yl)pip eridin-
4-
yl)pyrrolidin-3-yl)oxy)-3-((2,2,2-trifluoroethyl)amino)propan-2-yl)amino)-4-
(trifluoromethyl)pyridazin-3(2H)-one;
5-(((S)-1 -hy droxy -3-(((R)-2-oxo-1 -(1 -(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-
yl)py rrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3 (2H)-
one;
5-(((S)-1-(((S)-1-((3R,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-
4-y1)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-
3(2H)-one;
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5-(((S)-1-(((R)-1-((3S,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-
4-y1)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-
3(2H)-one;
5-(((2S)-1-((1-((3R,4R)-3-hydroxy-1-(5-(trifluoromethyppyrimidin-2-yOpiperidin-
4-
y1)-2-oxopyrrolidin-3-y0oxy)propan-2-y0oxy)-4-(trifluoromethyppyridazin-3(2H)-
one;
N-((S)-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyppyrimidin-2-yOpiperidin-4-
yOpyrrolidin-3-y0oxy)-2-46-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-
yl)amino)propyl)acetamide;
5-(((2R,3R)-3-hydroxy-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)butan-2-yl)amino)-4-
(trifluoromethyl)pyridazin-3(2H)-
one;
4-((R)-2-oxo-3-((S)-2-46-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-
yl)amino)prop oxy)py rroli din-1 -y1)-1-(5 -(trifluoromethyl)pyrimi din-2-
yl)piperi dine-3 -
carboxamide; and
4-((R)-2-oxo-3-((S)-2-46-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-
yl)amino)prop oxy)py rroli din-1 -y1)-1-(5 -(trifluoromethyl)pyrimi din-2-
yl)piperi dine-3 -
carbonitrile;
or a pharmaceutically acceptable salt of any of the aforementioned.
It is further appreciated that certain features of the invention, which are,
for clarity,
described in the context of separate embodiments, can also be provided in
combination in a
single embodiment. Conversely, various features of the invention which are,
for brevity,
described in the context of a single embodiment, can also be provided
separately or in any
suitable subcombination.
At various places in the present specification, substituents of compounds of
the
invention are disclosed in groups or in ranges. It is specifically intended
that the invention
include each and every individual subcombination of the members of such groups
and ranges.
For example, the term "C1-6 alkyl" is specifically intended to individually
disclose methyl,
ethyl, C3 alkyl, C4 alkyl, Cs alkyl, and C6 alkyl.
At various places in the present specification various aryl, heteroaryl,
cycloalkyl, and
heterocycloalkyl rings are described. Unless otherwise specified, these rings
can be attached
to the rest of the molecule at any ring member as permitted by valency. For
example, the
term "pyridinyl," "pyridyl," or "a pyridine ring" may refer to a pyridin-2-yl,
pyridin-3-yl, or
pyridin-4-y1 ring.
The term "n-membered," where "n" is an integer, typically describes the number
of
ring-forming atoms in a moiety where the number of ring-forming atoms is "n".
For
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example, piperidinyl is an example of a 6-membered heterocycloalkyl ring,
pyrazolyl is an
example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered
heteroaryl
ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered
cycloalkyl group.
For compounds of the invention in which a variable appears more than once,
each
variable can be a different moiety independently selected from the group
defining the
variable. For example, where a structure is described having two R groups that
are
simultaneously present on the same compound, the two R groups can represent
different
moieties independently selected from the group defined for R.
As used herein, the phrase "optionally substituted" means unsubstituted or
substituted.
As used herein, the term "substituted" means that a hydrogen atom is replaced
by a
non-hydrogen group. It is to be understood that substitution at a given atom
is limited by
valency.
As used herein, the term "C-j," where i and j are integers, employed in
combination
with a chemical group, designates a range of the number of carbon atoms in the
chemical
group with i-j defining the range. For example, C1-6 alkyl refers to an alkyl
group having 1, 2,
3, 4, 5, or 6 carbon atoms.
As used herein, the term "alkyl," employed alone or in combination with other
terms,
refers to a saturated hydrocarbon group that may be straight-chain or
branched. In some
embodiments, the alkyl group contains 1 to 7, 1 to 6, 1 to 4, or 1 to 3 carbon
atoms.
Examples of alkyl moieties include, but are not limited to, chemical groups
such as methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-
pentyl, 2-methyl-1-butyl,
3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, n-heptyl, and the like. In some
embodiments, the
alkyl group is methyl, ethyl, or propyl.
As used herein, "halo" or "halogen", employed alone or in combination with
other
terms, includes fluoro, chloro, bromo, and iodo. In some embodiments, halo is
F or Cl.
As used herein, the term "haloalkyl," employed alone or in combination with
other
terms, refers to an alkyl group having up to the full valency of halogen atom
substituents,
which may either be the same or different. In some embodiments, the halogen
atoms are
fluoro atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon
atoms.
Example haloalkyl groups include CF3, C2F5, CHF2, CC13, CHC12, C2C15, and the
like.
As used herein, the term "alkoxy," employed alone or in combination with other
terms, refers to a group of formula -0-alkyl. Example alkoxy groups include
methoxy,
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ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. In
some
embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
As used herein, "haloalkoxy," employed alone or in combination with other
terms,
refers to a group of formula -0-(haloalkyl). In some embodiments, the alkyl
group has 1 to 6
or 1 to 4 carbon atoms. An example haloalkoxy group is -0CF3.
As used herein, "amino," employed alone or in combination with other terms,
refers
to NH2.
As used herein, the term "alkylamino," employed alone or in combination with
other
terms, refers to a group of formula -NH(alkyl). In some embodiments, the
alkylamino group
has 1 to 6 or 1 to 4 carbon atoms. Example alkylamino groups include
methylamino,
ethylamino, propylamino (e.g., n-propylamino and isopropylamino), and the
like.
As used herein, the term "dialkylamino," employed alone or in combination with
other terms, refers to a group of formula -N(alkyl)2. Example dialkylamino
groups include
dimethylamino, diethylamino, dipropylamino (e.g., di(n-propyl)amino and
di(isopropyl)amino), and the like. In some embodiments, each alkyl group
independently has
1 to 6 or 1 to 4 carbon atoms.
As used herein, the term "heterocycloalkyl," employed alone or in combination
with
other terms, refers to a non-aromatic ring or ring system, which may
optionally contain one
or more alkenylene or alkynylene groups as part of the ring structure, which
has at least one
.. heteroatom ring member independently selected from nitrogen, sulfur,
oxygen, and
phosphorus. Heterocycloalkyl groups can include mono- or polycyclic (e.g.,
having 2, 3 or 4
fused, bridged, or spiro rings) ring systems. In some embodiments, the
heterocycloalkyl
group is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms
independently
selected from nitrogen, sulfur and oxygen. Also included in the definition of
.. heterocycloalkyl are moieties that have one or more aromatic rings (e.g.,
aryl or heteroaryl
rings) fused (i.e., having a bond in common with) to the non-aromatic
heterocycloalkyl ring,
for example, 1,2,3,4-tetrahydro-quinoline and the like. Heterocycloalkyl
groups can also
include bridgehead heterocycloalkyl groups (e.g., a heterocycloalkyl moiety
containing at
least one bridgehead atom, such as azaadmantan-l-yl and the like) and
spiroheterocycloalkyl
.. groups (e.g., a heterocycloalkyl moiety containing at least two rings fused
at a single atom,
such as [1,4-dioxa-8-aza-spiro[4.51decan-N-yll and the like). In some
embodiments, the
heterocycloalkyl group has 3 to 10 ring-forming atoms, 4 to 10 ring-forming
atoms, or about
3 to 8 ring forming atoms. In some embodiments, the heterocycloalkyl group has
2 to 20
carbon atoms, 2 to 15 carbon atoms, 2 to 10 carbon atoms, or about 2 to 8
carbon atoms. In
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some embodiments, the heterocycloalkyl group has 1 to 5 heteroatoms, 1 to 4
heteroatoms, 1
to 3 heteroatoms, or 1 to 2 heteroatoms. The carbon atoms or heteroatoms in
the ring(s) of
the heterocycloalkyl group can be oxidized to form a carbonyl, an N-oxide, or
a sulfonyl
group (or other oxidized linkage) or a nitrogen atom can be quaternized. In
some
embodiments, the heterocycloalkyl portion is a C2-7 monocyclic
heterocycloalkyl group. In
some embodiments, the heterocycloalkyl group is a morpholine ring, pyrrolidine
ring,
piperazine ring, piperidine ring, tetrahydropyran ring, tetrahyropyridine,
azetidine ring, or
tetrahydrofuran ring.
As used herein, the term "heterocycloalkylalkyl," employed alone or in
combination
with other terms, refers to a group of formula heterocycloalkyl-alkyl-. In
some embodiments,
the alkyl portion has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom(s). In some
embodiments, the
alkyl portion is methylene. In some embodiments, the heterocycloalkyl portion
has 3 to 10
ring members, 4 to 10 ring members, or 3 to 7 ring members. In some
embodiments, the
heterocycloalkyl group is monocyclic or bicyclic. In some embodiments, the
heterocycloalkyl portion is monocyclic. In some embodiments, the
heterocycloalkyl portion
is a C27 monocyclic heterocycloalkyl group.
As used herein, the term "aryl," employed alone or in combination with other
terms,
refers to a monocyclic or polycyclic (e.g., a fused ring system) aromatic
hydrocarbon moiety,
such as, but not limited to, phenyl, 1-naphthyl, 2-naphthyl, and the like. In
some
embodiments, aryl groups have from 6 to 10 carbon atoms or 6 carbon atoms. In
some
embodiments, the aryl group is a monocyclic or bicyclic group. In some
embodiments, the
aryl group is phenyl or naphthyl.
As used herein, the term "arylalkyl," employed alone or in combination with
other
terms, refers to a group of formula aryl-alkyl-. In some embodiments, the
alkyl portion has 1
to 4, 1 to 3, 1 to 2, or 1 carbon atom(s). In some embodiments, the alkyl
portion is
methylene. In some embodiments, the aryl portion is phenyl. In some
embodiments, the aryl
group is a monocyclic or bicyclic group. In some embodiments, the arylalkyl
group is benzyl.
As used herein, the term "heteroaryl," employed alone or in combination with
other
terms, refers to a monocyclic or polycyclic (e.g., a fused ring system)
aromatic hydrocarbon
moiety, having one or more heteroatom ring members independently selected from
nitrogen,
sulfur and oxygen. In some embodiments, the heteroaryl group is a monocyclic
or a bicyclic
group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen,
sulfur and
oxygen. Example heteroaryl groups include, but are not limited to, pyridyl,
pyrimidinyl,
pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, imidazolyl, thiazolyl,
indolyl, pyrryl,
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oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl,
triazolyl, tetrazolyl,
indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl,
benzimidazolyl, indolinyl,
pyrrolyl, azolyl, quinolinyl, isoquinolinyl, benzisoxazolyl, imidazo[1,2-
bithiazoly1 or the like.
The carbon atoms or heteroatoms in the ring(s) of the heteroaryl group can be
oxidized to
form a carbonyl, an N-oxide, or a sulfonyl group (or other oxidized linkage)
or a nitrogen
atom can be quatemized, provided the aromatic nature of the ring is preserved.
In some
embodiments, the heteroaryl group has from 3 to 10 carbon atoms, from 3 to 8
carbon atoms,
from 3 to 5 carbon atoms, from 1 to 5 carbon atoms, or from 5 to 10 carbon
atoms. In some
embodiments, the heteroaryl group contains 3 to 14, 4 to 12, 4 to 8, 9 to 10,
or 5 to 6 ring-
forming atoms. In some embodiments, the heteroaryl group has 1 to 4, 1 to 3,
or 1 to 2
heteroatoms.
As used herein, the term "heteroarylalkyl," employed alone or in combination
with
other terms, refers to a group of formula heteroaryl-alkyl-. In some
embodiments, the alkyl
portion has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom(s). In some embodiments,
the alkyl portion
is methylene. In some embodiments, the heteroaryl portion is a monocyclic or
bicyclic group
having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur
and oxygen. In
some embodiments, the heteroaryl portion has 5 to 10 carbon atoms.
The compounds described herein can be asymmetric (e.g., having one or more
stereocenters). All stereoisomers, such as enantiomers and diastereomers, are
intended unless
otherwise indicated. Compounds of the present invention that contain
asymmetrically
substituted carbon atoms can be isolated in optically active or racemic forms.
Methods on
how to prepare optically active forms from optically inactive starting
materials are known in
the art, such as by resolution of racemic mixtures or by stereoselective
synthesis. Geometric
isomers of olefins, C=N double bonds, and the like can also be present in the
compounds
described herein, and all such stable isomers are contemplated in the present
invention. Cis
and trans geometric isomers of the compounds of the present invention may be
isolated as a
mixture of isomers or as separated isomeric forms.
Compounds of the invention also include tautomeric forms. Tautomeric forms
result
from the swapping of a single bond with an adjacent double bond together with
the
concomitant migration of a proton. Tautomeric forms include prototropic
tautomers which
are isomeric protonation states having the same empirical formula and total
charge. Example
prototropic tautomers include ketone ¨ enol pairs, amide - imidic acid pairs,
lactam ¨ lactim
pairs, enamine ¨ imine pairs, and annular forms where a proton can occupy two
or more
positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H-
and 4H-
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1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole. Tautomeric
forms can be in
equilibrium or sterically locked into one form by appropriate substitution. An
example of
tautomeric forms, pyridazin-3(211)-one and pyridazin-3-ol, is depicted below:
O HO
pyridazin-3(21/)-one pyridazin-3-ol
Compounds of the invention also include all isotopes of atoms occurring in the
intermediates or final compounds. Isotopes include those atoms having the same
atomic
number but different mass numbers. For example, isotopes of hydrogen include
tritium and
deuterium. In some embodiments, the compounds of the invention include at
least one
deuterium atom.
The term, "compound," as used herein is meant to include all stereoisomers,
geometric iosomers, tautomers, and isotopes of the structures depicted, unless
otherwise
specified.
All compounds, and pharmaceutically acceptable salts thereof, can be found
together
with other substances such as water and solvents (e.g., in the form of
hydrates and solvates)
or can be isolated.
In some embodiments, the compounds of the invention, or salts thereof, are
substantially isolated. By "substantially isolated" is meant that the compound
is at least
partially or substantially separated from the environment in which it was
formed or detected.
Partial separation can include, for example, a composition enriched in the
compounds of the
invention. Substantial separation can include compositions containing at least
about 50%, at
least about 60%, at least about 70%, at least about 80%, at least about 90%,
at least about
95%, at least about 97%, or at least about 99% by weight of the compounds of
the invention,
or salt thereof Methods for isolating compounds and their salts are routine in
the art.
The phrase "pharmaceutically acceptable" is employed herein to refer to those
compounds, materials, compositions, and/or dosage forms which are, within the
scope of
sound medical judgment, suitable for use in contact with the tissues of human
beings and
animals without excessive toxicity, irritation, allergic response, or other
problem or
complication, commensurate with a reasonable benefit/risk ratio.
The present invention also includes pharmaceutically acceptable salts of the
compounds described herein. As used herein, "pharmaceutically acceptable
salts" refers to
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derivatives of the disclosed compounds wherein the parent compound is modified
by
converting an existing acid or base moiety to its salt form. Examples of
pharmaceutically
acceptable salts include, but are not limited to, mineral or organic acid
salts of basic residues
such as amines; alkali or organic salts of acidic residues such as carboxylic
acids; and the
like. The pharmaceutically acceptable salts of the present invention include
the non-toxic
salts of the parent compound formed, for example, from non-toxic inorganic or
organic acids.
The pharmaceutically acceptable salts of the present invention can be
synthesized from the
parent compound which contains a basic or acidic moiety by conventional
chemical methods.
Generally, such salts can be prepared by reacting the free acid or base forms
of these
compounds with a stoichiometric amount of the appropriate base or acid in
water or in an
organic solvent, or in a mixture of the two. Lists of suitable salts are found
in Remington's
Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985,
p. 1418
and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is
incorporated herein by
reference in its entirety.
Synthesis
Compounds of the invention, including salts thereof, can be prepared using
known
organic synthesis techniques and can be synthesized according to any of
numerous possible
synthetic routes.
The reactions for preparing compounds of the invention can be carried out in
suitable
solvents which can be readily selected by one of skill in the art of organic
synthesis. Suitable
solvents can be substantially nonreactive with the starting materials
(reactants), the
intermediates, or products at the temperatures at which the reactions are
carried out, e.g.,
temperatures which can range from the solvent's freezing temperature to the
solvent's boiling
temperature. A given reaction can be carried out in one solvent or a mixture
of more than one
solvent. Depending on the particular reaction step, suitable solvents for a
particular reaction
step can be selected by the skilled artisan.
Preparation of compounds of the invention can involve the protection and
deprotection of various chemical groups. The need for protection and
deprotection, and the
selection of appropriate protecting groups, can be readily determined by one
skilled in the art.
The chemistry of protecting groups can be found, for example, in T.W. Greene
and P.G.M.
Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, Inc.,
New York
(1999), which is incorporated herein by reference in its entirety.
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Reactions can be monitored according to any suitable method known in the art.
For
example, product formation can be monitored by spectroscopic means, such as
nuclear
magnetic resonance spectroscopy (e.g., 1H or 13C), infrared spectroscopy,
spectrophotometry
(e.g., UV-visible), or mass spectrometry, or by chromatography such as high
performance
liquid chromatography (HPLC) or thin layer chromatography.
The expressions, "ambient temperature," "room temperature," and "RT", as used
herein, are understood in the art, and refer generally to a temperature, e.g.
a reaction
temperature, that is about the temperature of the room in which the reaction
is carried out, for
example, a temperature from about 20 C to about 30 C.
Compounds of Formula I can be prepared according to numerous preparatory
routes
known in the literature. Example synthetic methods for preparing compounds of
the invention
are provided in the Schemes below. Unless noted otherwise, all substituents
are as defined
herein.
In the process depicted in Scheme 1, an appropriately substituted, halogen
containing
compound (i.e.,Xa = Cl or Br) of Formula (1-1) is protected as the
p¨methoxybenzyl ether
("PMB") compound of Formula (1-2) by treatment with p-methoxybenzyl chloride
("PMB-
C1") in the presence of sodium hydride (NaH).
Scheme 1
CI
0 0
X
HN OMe PMB
NaH
Xa Xa
(1-1) (1-2)
Compound of Formula (1-2) can be reacted with a variety of nucleophiles to
provide
compounds of Formula (I) following deprotection of the PMB protecting group,
as shown in
Schemes 2-4.
In the process depicted in Scheme 2, the compound of Formula (1-3) (wherein Ya
is
0, NR, or S) is reacted with a compound having Formula (1-2) in the presence
of a base
(e.g., triethylamine, Cs2CO3, or potassium tert-butoxide) to provide a
compound of formula
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(1-4). Deprotection with an acid (e.g., trifluoromethane sulfonic acid in
trifluoroacetic acid or
hydrochloric acid) provides a compound of Formula (IA).
Scheme 2
/ / R1 R2\ R5R6 R7R8 Rii R, _
V /
__________________________________________________________ D 1\1 ( L)¨Z
R3 R4 R9 R19 _I a
\ in \ /ID
(1-3)
0
,i/ PMB X
N
I (1-2)
N
0 Xa
PMB X 7
N / R1 R2\ R5 R6 R7R8 11 12
I 1
C
N
y) D N ( I_)¨Z
ya m y2
q r a
R3 R4 \ R9 R5
(1-4) \ in / ID
Acid
0
HN 1 / RiR2\ R5R8 R7R8 Rii Ri_
(1_Z
R3 R4 R9 R19
(IA) \ in \ /ID
Methods of Use
Compounds of the invention can inhibit the activity of PARP7. For example, the
compounds of the invention can be used to inhibit activity of PARP7 in a cell
or in an
individual or patient in need of inhibition of the enzyme by administering an
inhibiting
amount of a compound of the invention to the cell, individual, or patient.
As PARP7 inhibitors, the compounds of the invention are useful in the
treatment of
various diseases associated with abnormal expression or activity of PARP7. For
example, the
compounds of the invention are useful in the treatment of cancer. In some
embodiments, the
cancers treatable according to the present invention include breast, central
nervous system,
endometrium, kidney, large intestine, lung, oesophagus, ovary, pancreas,
prostate, stomach,
head and neck (upper aerodigestive), urinary tract, colon, and others.
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In some embodiments, the cancers treatable according to the present invention
include
hematopoietic malignancies such as leukemia and lymphoma. Example lymphomas
include
Hodgkin's or non-Hodgkin's lymphoma, multiple myeloma, B-cell lymphoma (e.g.,
diffuse
large B-cell lymphoma (DLBCL)), chronic lymphocytic lymphoma (CLL), T-cell
lymphoma,
hairy cell lymphoma, and Burkett's lymphoma. Example leukemias include acute
lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), chronic
lymphocytic
leukemia (CLL), and chronic myelogenous leukemia (CML).
Other cancers treatable by the administration of the compounds of the
invention
include liver cancer (e.g., hepatocellular carcinoma), bladder cancer, bone
cancer, glioma,
.. breast cancer, cervical cancer, colon cancer, endometrial cancer,
epithelial cancer, esophageal
cancer, Ewing's sarcoma, pancreatic cancer, gallbladder cancer, gastric
cancer,
gastrointestinal tumors, head and neck cancer (upper aerodigestive cancer),
intestinal cancers,
Kaposi's sarcoma, kidney cancer, laryngeal cancer, liver cancer (e.g.,
hepatocellular
carcinoma), lung cancer, prostate cancer, rectal cancer, skin cancer, stomach
cancer,
.. testicular cancer, thyroid cancer, and uterine cancer.
In some embodiments, the cancer treatable by administration of the compounds
of the
invention is multiple myeloma, DLBCL, hepatocellular carcinoma, bladder
cancer,
esophageal cancer, head and neck cancer (upper aerodigestive cancer), kidney
cancer,
prostate cancer, rectal cancer, stomach cancer, thyroid cancer, uterine
cancer, and breast
.. cancer.
The PARP7 inhibitors of the invention may also have therapeutic utility in
PARP7-
related disorders in disease areas such as cardiology, virology,
neurodegeneration,
inflammation, and pain, particularly where the diseases are characterized by
overexpression
or increased activity of PARP7.
As used herein, the term "cell" is meant to refer to a cell that is in vitro,
ex vivo or in
vivo. In some embodiments, an ex vivo cell can be part of a tissue sample
excised from an
organism such as a mammal. In some embodiments, an in vitro cell can be a cell
in a cell
culture. In some embodiments, an in vivo cell is a cell living in an organism
such as a
mammal.
As used herein, the term "contacting" refers to the bringing together of
indicated
moieties in an in vitro system or an in vivo system. For example, "contacting"
PARP7 or
"contacting" a cell with a compound of the invention includes the
administration of a
compound of the present invention to an individual or patient, such as a
human, having
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PARP7, as well as, for example, introducing a compound of the invention into a
sample
containing a cellular or purified preparation containing PARP7.
As used herein, the term "individual" or "patient," used interchangeably,
refers to
mammals, and particularly humans.
As used herein, the phrase "therapeutically effective amount" refers to the
amount of
active compound or pharmaceutical agent that elicits the biological or
medicinal response in a
tissue, system, animal, individual or human that is being sought by a
researcher, veterinarian,
medical doctor or other clinician.
As used herein the term "treating" or "treatment" refers to 1) inhibiting the
disease in
an individual who is experiencing or displaying the pathology or
symptomatology of the
disease (i.e., arresting further development of the pathology and/or
symptomatology), or 2)
ameliorating the disease in an individual who is experiencing or displaying
the pathology or
symptomatology of the disease (i.e., reversing the pathology and/or
symptomatology).
As used herein the term "preventing" or "prevention" refers to preventing the
disease
in an individual who may be predisposed to the disease but does not yet
experience or display
the pathology or symptomatology of the disease.
Combination Therapy
One or more additional pharmaceutical agents or treatment methods such as, for
example, chemotherapeutics or other anti-cancer agents, immune enhancers,
immunosuppressants, immunotherapies, radiation, anti-tumor and anti-viral
vaccines,
cytokine therapy (e.g., IL2, GM-CSF, etc.), and/or kinase (tyrosine or
serine/threonine),
epigenetic or signal transduction inhibitors can be used in combination with
the compounds
of the present invention. The agents can be combined with the present
compounds in a single
dosage form, or the agents can be administered simultaneously or sequentially
as separate
dosage forms.
Suitable agents for use in combination with the compounds of the present
invention
for the treatment of cancer include chemotherapeutic agents, targeted cancer
therapies,
immunotherapies or radiation therapy. Compounds of this invention may be
effective in
combination with anti-hormonal agents for treatment of breast cancer and other
tumors.
Suitable examples are anti-estrogen agents including but not limited to
tamoxifen and
toremifene, aromatase inhibitors including but not limited to letrozole,
anastrozole, and
exemestane, adrenocorticosteroids (e.g. prednisone), progestins (e.g.
megastrol acetate), and
estrogen receptor antagonists (e.g. fulvestrant). Suitable anti-hormone agents
used for
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treatment of prostate and other cancers may also be combined with compounds of
the present
invention. These include anti-androgens including but not limited to
flutamide, bicalutamide,
and nilutamide, luteinizing hormone-releasing hormone (LHRH) analogs including
leuprolide, goserelin, triptorelin, and histrelin, LHRH antagonists (e.g.
degarelix), androgen
receptor blockers (e.g. enzalutamide) and agents that inhibit androgen
production (e.g.
abiraterone).
Angiogenesis inhibitors may be efficacious in some tumors in combination with
FGFR inhibitors. These include antibodies against VEGF or VEGFR or kinase
inhibitors of
VEGFR. Antibodies or other therapeutic proteins against VEGF include
bevacizumab and
aflibercept. Inhibitors of VEGFR kinases and other anti-angiogenesis
inhibitors include but
are not limited to sunitinib, sorafenib, axitinib, cediranib, pazopanib,
regorafenib, brivanib,
and vandetanib
Suitable chemotherapeutic or other anti-cancer agents include, for example,
alkylating
agents (including, without limitation, nitrogen mustards, ethylenimine
derivatives, alkyl
sulfonates, nitrosoureas and triazenes) such as uracil mustard, chlormethine,
cyclophosphamide (CytoxanTm), ifosfamide, melphalan, chlorambucil, pipobroman,
triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine,
lomustine,
streptozocin, dacarbazine, and temozolomide.
Other anti-cancer agent(s) include antibody therapeutics to checkpoint or
costimulatory molecules such as CTLA-4, PD-1, PD-Li or 4-1BB, respectively, or
antibodies
to cytokines (IL-10, TGF-P, etc.). Exemplary cancer immunotherapy antibodies
include
pembrolizumab, ipilimumab, nivolumab, atezolizumab and durvalumab. Additional
anti-
cancer agent(s) include antibody therapeutics directed to surface molecules of
hematological
cancers such as ofatumumab, ritthximab and alemtuzumab.
Methods for the safe and effective administration of most of these
chemotherapeutic
agents are known to those skilled in the art. In addition, their
administration is described in
the standard literature. For example, the administration of many of the
chemotherapeutic
agents is described in the "Physicians' Desk Reference" (PDR, e.g., 1996
edition, Medical
Economics Company, Montvale, NJ), the disclosure of which is incorporated
herein by
reference as if set forth in its entirety.
Pharmaceutical Formulations and Dosage Forms
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When employed as pharmaceuticals, the compounds of the invention can be
administered in the form of pharmaceutical compositions. A pharmaceutical
composition
refers to a combination of a compound of the invention, or its
pharmaceutically acceptable
salt, and at least one pharmaceutically acceptable carrier. These compositions
can be prepared
in a manner well known in the pharmaceutical art, and can be administered by a
variety of
routes, depending upon whether local or systemic treatment is desired and upon
the area to be
treated. Administration may be oral, topical (including ophthalmic and to
mucous
membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g.,
by inhalation
or insufflation of powders or aerosols, including by nebulizer; intratracheal,
intranasal,
epidermal and transdermal), ocular, or parenteral.
This invention also includes pharmaceutical compositions which contain, as the
active
ingredient, one or more of the compounds of the invention above in combination
with one or
more pharmaceutically acceptable carriers. In making the compositions of the
invention, the
active ingredient is typically mixed with an excipient, diluted by an
excipient or enclosed
within such a carrier in the form of, for example, a capsule, sachet, paper,
or other container.
When the excipient serves as a diluent, it can be a solid, semi-solid, or
liquid material, which
acts as a vehicle, carrier or medium for the active ingredient. Thus, the
compositions can be
in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs,
suspensions,
emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium),
ointments
containing, for example, up to 10 % by weight of the active compound, soft and
hard gelatin
capsules, suppositories, sterile injectable solutions, and sterile packaged
powders.
The compositions can be formulated in a unit dosage form. The term "unit
dosage
form" refers to a physically discrete unit suitable as unitary dosages for
human subjects and
other mammals, each unit containing a predetermined quantity of active
material calculated
to produce the desired therapeutic effect, in association with a suitable
pharmaceutical
excipient.
The active compound can be effective over a wide dosage range and is generally
administered in a pharmaceutically effective amount. It will be understood,
however, that the
amount of the compound actually administered will usually be determined by a
physician,
according to the relevant circumstances, including the condition to be
treated, the chosen
route of administration, the actual compound administered, the age, weight,
and response of
the individual patient, the severity of the patient's symptoms, and the like.
For preparing solid compositions such as tablets, the principal active
ingredient is
mixed with a pharmaceutical excipient to form a solid pre-formulation
composition
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containing a homogeneous mixture of a compound of the present invention. When
referring
to these pre-formulation compositions as homogeneous, the active ingredient is
typically
dispersed evenly throughout the composition so that the composition can be
readily
subdivided into equally effective unit dosage forms such as tablets, pills and
capsules. This
solid pre-formulation is then subdivided into unit dosage forms of the type
described above
containing from, for example, 0.1 to about 500 mg of the active ingredient of
the present
invention.
The tablets or pills of the present invention can be coated or otherwise
compounded to
provide a dosage form affording the advantage of prolonged action. For
example, the tablet or
.. pill can comprise an inner dosage and an outer dosage component, the latter
being in the form
of an envelope over the former. The two components can be separated by an
enteric layer
which serves to resist disintegration in the stomach and permit the inner
component to pass
intact into the duodenum or to be delayed in release. A variety of materials
can be used for
such enteric layers or coatings, such materials including a number of
polymeric acids and
mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and
cellulose
acetate.
The liquid forms in which the compounds and compositions of the present
invention
can be incorporated for administration orally or by injection include aqueous
solutions,
suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions
with edible oils
such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as
elixirs and similar
pharmaceutical vehicles.
Compositions for inhalation or insufflation include solutions and suspensions
in
pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof,
and powders.
The liquid or solid compositions may contain suitable pharmaceutically
acceptable excipients
as described supra. In some embodiments, the compositions are administered by
the oral or
nasal respiratory route for local or systemic effect. Compositions in can be
nebulized by use
of inert gases. Nebulized solutions may be breathed directly from the
nebulizing device or the
nebulizing device can be attached to a face masks tent, or intermittent
positive pressure
breathing machine. Solution, suspension, or powder compositions can be
administered orally
or nasally from devices which deliver the formulation in an appropriate
manner.
The amount of compound or composition administered to a patient will vary
depending upon what is being administered, the purpose of the administration,
such as
prophylaxis or therapy, the state of the patient, the manner of
administration, and the like. In
therapeutic applications, compositions can be administered to a patient
already suffering from
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a disease in an amount sufficient to cure or at least partially arrest the
symptoms of the
disease and its complications. Effective doses will depend on the disease
condition being
treated as well as by the judgment of the attending clinician depending upon
factors such as
the severity of the disease, the age, weight and general condition of the
patient, and the like.
The compositions administered to a patient can be in the form of
pharmaceutical
compositions described above. These compositions can be sterilized by
conventional
sterilization techniques, or may be sterile filtered. Aqueous solutions can be
packaged for use
as is, or lyophilized, the lyophilized preparation being combined with a
sterile aqueous carrier
prior to administration.
The therapeutic dosage of the compounds of the present invention can vary
according
to, for example, the particular use for which the treatment is made, the
manner of
administration of the compound, the health and condition of the patient, and
the judgment of
the prescribing physician. The proportion or concentration of a compound of
the invention in
a pharmaceutical composition can vary depending upon a number of factors
including
dosage, chemical characteristics (e.g., hydrophobicity), and the route of
administration. For
example, the compounds of the invention can be provided in an aqueous
physiological buffer
solution containing about 0.1 to about 10% w/v of the compound for parenteral
administration. Some typical dose ranges are from about 1 g/kg to about 1
g/kg of body
weight per day. In some embodiments, the dose range is from about 0.01 mg/kg
to about 100
mg/kg of body weight per day. The dosage is likely to depend on such variables
as the type
and extent of progression of the disease or disorder, the overall health
status of the particular
patient, the relative biological efficacy of the compound selected,
formulation of the
excipient, and its route of administration. Effective doses can be
extrapolated from dose-
response curves derived from in vitro or animal model test systems.
The compounds of the invention can also be formulated in combination with one
or
more additional active ingredients which can include any pharmaceutical agent
such as anti-
viral agents, anti-cancer agents, vaccines, antibodies, immune enhancers,
immune
suppressants, anti-inflammatory agents and the like.
EXAMPLES
Equipment: 1FINMR Spectra were recorded at 300 or 400 MHz using a Bruker
AVANCE 300
MHz/400 MHz spectrometer. NMR interpretation was performed using Bruker
Topspin
software to assign chemical shift and multiplicity. In cases where two
adjacent peaks of equal
41
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or unequal height were observed, these two peaks may be labeled as either a
multiplet or as a
doublet. In the case of a doublet, a coupling constant using this software may
be assigned. In
any given example, one or more protons may not be observed due to obscurity by
water
and/or solvent peaks. LCMS equipment and conditions are as follows:
1. LC (basic condition): Shimadzu LC-20AD, Binary Pump, Diode Array
Detector. Column: Kinetex 2.6 pm EVO C18 100A, 50*3.0 mm, 2.6 m.
Mobile phase: A: Water/5 mM NH4HCO3, B: Acetonitrile. Flow Rate: 1.2
mL/min at 40 C. Detector: 254 nm, 220 nm. Gradient stop time, 2.9 min.
Timetable:
T (min) A(%) B(%)
0.01 90 10
2.10 5 95
2.70 5 95
2.90 90 10
2. LC (basic condition): Shimadzu LC-20ADXR, Binary Pump, Diode Array
Detector, Column: Poroshell HPH-C18 50*3.0 mm, 2.7 m. Mobile Phase
A: 0.04% Ammonium hydroxide, Mobile Phase B: Acetonitrile. Flow
Rate:1.2 ml/min at 40 C. Detector: 254 nm, 220 nm. Gradient stop time
3.0 min Timetable:
T(min) A(%) B(%)
0.01 90 10
2.0 5 95
2.7 5 95
2.8 90 10
3. LC (acidic condition): Shimadzu LC-20AD, Binary Pump, Diode Array
Detector. Column: Ascentis Express C18, 50*3.0 mm, 2.7 m. Mobile
phase: A: Water/0.05% TFA, B: Acetonitrile/0.05%TFA. Flow Rate: 1.5
mL/min at 40 C. Detector: 254 nm, 220 nm. Gradient stop time, 2.9 min.
Timetable:
T (min) A(%) B(%)
42
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0.01 90 5
2.10 5 95
2.70 5 95
2.90 90 5
4. LC (acidic condition): Shimadzu LC-30AD, Binary Pump, Diode Array
Detector. Column: Accucore C18 50*2.1 mm, 2.6 p.m. Mobile Phase A:
Water/0.1% FA, Mobile Phase B: Acetonitrile/0.1%FA. Flow Rate:1.0
ml/min at 40 C. Detector: 254 nm, 220 nm. Gradient stop time 3.0 min.
Timetable:
T(min) A(%) B(%)
0.01 95 5
2.0 5 95
2.7 5 95
2.8 95 5
1. S:LCMS-2020, Quadrupole LC/MS, Ion Source: ES-API, TIC: 90-900
m/z, Fragmentor: 60, Drying gas flow: 15 L/min, Nebulizing Gas Flow:
1.5 L/min, Drying gas temperature: 250 C, Vcap: 1100V.
2. Sample preparation: samples were dissolved in ACN or methanol at 1-10
mg/mL, then filtered through a 0.22 pm filter membrane. Injection
volume: 1-10 pL.
Definitions: ACN (acetonitrile); CH3CN (acetonitrile); CDC13 (deuterated
chloroform);
CD3OD (deuterated methanol); DCM (dichloromethane); DEA (diethylamine); DIEA
(diisopropylethylamine); DMF (N,N-dimethylformamide); DMAP (4-dimethyl
aminopyridine); DMSO (dimethylsulfoxide); DMSO-d6(deuterated
dimethylsulfoxide);
equiv (equivalent); ESI (electrospray ionization); Et0Ac (ethyl acetate); Et0H
(ethanol); g
(gram); h (hour); HATU (1-Ibis(dimethylamino)methylene1-1H-1,2,3-triazolo[4,5-
blpyridinium 3-oxide hexafluorophosphate); 11-1NMR (proton nuclear magnetic
resonance);
HC1 (hydrochloric acid); Hz (hertz); H20 (water); Hex (hexanes); i-prOH
(isopropyl alcohol);
K2CO3(potassium carbonate); L (litre); LCMS (liquid chromatography-mass
spectrometry);
M (molar); MeCN (acetonitrile); Me0H (methanol); mg (milligrams); MHz
(megahertz); min
(minutes); MtBE (methyl tert-butyl ether); mL (millilitres), mmol
(millimoles); N (normal);
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NaBH(Ac0)3 (sodium triacetoxyborohydride); NaCl (sodium chloride); NaH (sodium
hydride); NaHCO3 (sodium bicarbonate); n-BuOH (n-butyl alcohol); NH4C1
(ammonium
chloride); NMP (N-methyl-2-pyrrolidone); PE (petroleum ether); PMB
(paramethoxy
benzyl); prep-HPLC (preparative high-performance liquid chromatography); RT
(room
temperature); TEA (triethylamine); TFA (trifluoroacetic acid); tR (retention
time); triflic
(trifluoromethane sulfonic); AcOH (acetic acid); HATU (1-
[Bis(dimethylamino)methylene]-
1H-1,2,3-triazolo[4,5-blpyridinium 3-oxide hexafluorophosphate); Na2CO3
(sodium
carbonate); NaBH3CN (sodium cyanoborohydride); NaOH (sodium hydroxide); NH3
(ammonia); Pd/C (palladium on carbon); PMB (p-methoxybenzyl); STAB (sodium
triacetoxyborohydride); t-BuOK (potassium tert-butoxide); TEMPO ((2,2,6,6-
Tetramethylpiperidin-1-yl)oxyl); Tf20 (trifluoromethanesulfonic anhydride);
TfOH (triflic
acid); THF (tetrahydrofuran); Ti(Oi-Pr)4 (titanium isopropoxide).
Intermediate I-I: Synthesis of 5-Chloro-2-(4-methoxybenzy1)-4-
(trifluoromethyl)pyridazin-3(2H)-one
0 0 0
NH A Br NPMB g Br)-LN ,PMB
Br'N
Br Me0
0 0 0
F3C)L ,PMB D
N F3CN,PMB E F3CLN,PMB
Me0- A\I
HO ci
Step A
To a solution of 4,5-dibromo-2,3-dihydropyridazin-3-one (250 g, 984.71 mmol, 1
equiv) in DMF (2.5 L) was added NaH (59.1 g, 1477.07 mmol, 1.50 equiv, 60%) in
several
.. batches at 0-10 C. followed by the addition of 1-(chloromethyl)-4-
methoxybenzene (230.3 g,
1470.53 mmol, 1.49 equiv) at 0 C. The resulting solution was stirred for 3 h
at RT. The
reaction was then quenched by the addition of 5 L of water/ice and extracted
with 2 x 2.5 L of
DCM. The organic layers were combined and concentrated. The solids were washed
by
Me0H (500 mL x 2) to afford 290 g (79% yield) of 4,5-dibromo-2-[(4-
.. methoxyphenyOmethyll-2,3-dihydropyridazin-3-one as a solid. LCMS [M+H]+
378.00.
Step B
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A solution of 4,5-dibromo-2-[(4-methoxyphenyOmethy11-2,3-dihydropyridazin-3-
one
(290 g, 775.33 mmol, 1 equiv) and potassium hydroxide (130.5 g, 2326.00 mmol,
3.00 equiv)
in Me0H (2.5 L) was stirred for 2 h at RT. The resulting mixture was
concentrated to 500
mL and the solids were collected by filtration. The resulting cake was
slurried for 1 h in water
(1L) to afford 232 g (92% yield) of 4-bromo-5-methoxy-2-[(4-
methoxyphenyOmethy11-2,3-
dihydropyridazin-3-one as a solid. LCMS [MA-11+326.90.
Step C
A solution of 4-bromo-5-methoxy-2-[(4-methoxyphenyOmethy11-2,3-
dihydropyridazin-3-one (232 g, 713.49 mmol, 1 equiv), methyl 2,2-difluoro-2-
sulfoacetate
(411.2 g, 2140.44 mmol, 3.00 equiv), and Cul (67.9 g, 356.52 mmol, 0.50 equiv)
in NMP
(1.2L) was stirred for 3 h at 100 C. The reaction was then quenched by the
addition of 1.5L
of water. The resulting solution was extracted with 3 x 1L of DCM. The organic
layers were
combined and concentrated. The residue was applied onto a silica gel column
with
Et0Ac/petroleum ether (1/1). The collected fractions were combined and
concentrated to
afford the crude oil to which was added 1L of water. The solids were collected
by filtration
and washed with 100 mL of Me0H to afford 170 g (76% yield) of 5-methoxy-2-[(4-
methoxyphenyOmethy11-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one as a
solid. LCMS
[M+Hr 315.10.
Step D
To a solution of 5-methoxy-2-[(4-methoxyphenyOmethy11-4-(trifluoromethyl)-2,3-
dihydropyridazin-3-one (170 g, 540.95 mmol, 1 equiv) in DMF (850 mL) was added
TMSI
(140 g, 699.67 mmol, 1.29 equiv) dropwise at 20 C. The resulting solution was
stirred for 20
h at 85 C. The reaction mixture was then quenched by the addition of 850 mL
of water and
the resulting solution was extracted with 3 x 850 mL of DCM and the organic
layers
combined and dried over anhydrous sodium sulfate. The organic layers were
concentrated
under vacuum and the crude product was purified by silica gel column
chromatography and
then recrystallized with MtBE to afford 120 g (74% yield) of 5-hydroxy-2-[(4-
methoxyphenyOmethy11-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one as a white
solid.
LCMS [M-411+ 301.07.
Step E
To a solution of 5-hydroxy-2-[(4-methoxyphenyOmethy11-4-(trifluoromethyl)-2,3-
dihydropyridazin-3-one (110 g, 366.38 mmol, 1 equiv) in DMF (550 mL) was added
oxalic
dichloride (93 g, 732.75 mmol, 2.00 equiv) dropwise at 0 - 5 C. The resulting
solution was
stirred for 8 h at RT. The reaction was then quenched by the addition of 550
mL of water.
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The solids were collected by filtration to afford 108 g (93%) of 5-chloro-2-
[(4-
methoxyphenyOmethyll-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one as a white
solid.
LCMS [M+Hl+ 319.04 [M+H1+,1FINMR (30 MHz, DMSO-d6) 6 8.22 (d, J = 0.8 Hz, 1H),
7.33 ¨7.22 (m, 2H), 6.94 ¨ 6.84 (m, 2H), 5.18 (s, 2H), 3.71 (s, 3H).
Intermediate 1-2: Synthesis of (S)-2-(2-01-(4-methoxybenzy1)-6-oxo-5-
(trifluoromethyl)-
1,6-dihydropyridazin-4-yDamino)propoxy)acetic acid
Boc,NH Boc,NH HCI
0 NH2
A
0õ.0H µs". ).LOH
0
F3CAN,PMB
NI
0
\`µµ. J.LOH
Step A
To a solution of tert-butyl (S)-(1-hydroxypropan-2-yl)carbamate (5.00 g, 28.5
mmol,
1.0 equiv) in DMF at 0 C (80 mL) was added NaH (60% dispersion in oil, 3.4 g,
85.6 mmol,
3.0 equiv) batchwise. The mixture was stirred for 20 min at that temperature
and to this
suspension was added tert-butyl 2-bromoacetate (7.30 g, 57 mmol, 2.00 equiv).
The resulting
solution was stirred for 30 min at 0 C and then water (60 mL) was added. The
solution was
extracted with 3 x 100 mL of ethyl acetate. The organic layers were combined
and washed
with 3 x 50 mL of brine. The organic layers were dried over magnesium sulfate,
filtered, and
concentrated in vacuo. The crude product was applied onto a silica gel column
eluting with
ethyl acetate/petroleum ether (3:7) to afford 2.8 g (34% yield) of tert-butyl
(S)-2-(2-((tert-
butoxycarbonyl)amino)propoxy)acetate as a colorless oil. LCMS (ESI, m/z):
290.20 [M+1-1]+.
Step B
A solution of tert-butyl 2-[(2S)-2-[(tert-butoxycarbonyl)aminolpropoxy]acetate
(2.80
g, 9.7 mmol, 1.0 equiv) in 4N HC1 in dioxane (30 mL) was stirred for 14 hours
at room
temperature. The mixture was concentrated to afford 2.5 g of crude (S)-2-(2-
aminopropoxy)acetic acid hydrochloride as a red oil. LCMS (ESI, m/z): 133.15
[M+1-1]+.
Step C
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A solution of 5-chloro-2-(4-methoxybenzy1)-4-(trifluoromethyl)pyridazin-3(2H)-
one
(3.00 g, 9.4 mmol, 1.00 equiv; Intermediate I-1), TEA (2.86 g, 28.2 mmol, 3.0
equiv), and
(S)-2-(2-aminopropoxy)acetic acid hydrochloride (2.50 g, 14.7 mmol, 1.6 equiv)
in i-PrOH
(100 mL) was stirred for 2 hours at 60 C. The mixture was concentrated and
the crude
product was applied onto a silica gel column eluting with
dichloromethane/methanol (10:1) to
afford 1.9 g (49% yield) of (S)-2-(2-((1-(4-methoxybenzy1)-6-oxo-5-
(trifluoromethyl)-1,6-
dihydropyridazin-4-yl)amino)propoxy)acetic acid as a yellow oil. LCMS (ESI,
m/z): 415.2
[M+H]+.
Intermediate 1-3: Synthesis of 3-hydroxy-1-(piperidin-4-yl)pyrrolidin-2-one
hydrochloride
A 0 ,c2),Boc
HCI
_________________________________ HO5
01H
0 0
0
Step A
A solution of 2-(2,2-dimethy1-5-oxo-1,3-dioxolan-4-yOacetaldehyde (6.00 g,
37.9
mmol, 1.0 equiv), acetic acid (2.73g, 45.5 mmol, 1.2 equiv), and tert-butyl 4-
aminopiperidine-l-carboxylate (15.2 g, 75.9 mmol, 2.0 equiv) in DCE (100 mL)
was stirred
for 1 hour and then STAB (24.0 grams, 114 mmol, 3.0 equiv) was added. The
resulting
solution was stirred for 14 hours at room temperature. The pH value of the
solution was
adjusted to pH 8 with saturated aqueous sodium bicarbonate solution. The
resulting solution
was extracted with 3 x 100 mL of dichloromethane. The organic layers were
combined and
.. washed with 50 mL of 10% aqueous citric acid and 50 mL of brine. The
organic layers were
dried over anhydrous sodium sulfate, filtered, and concentrated. The residue
was applied onto
a silica gel column eluting with ethyl acetate/petroleum ether (8:2) to give
5.1 g (47% yield)
of tert-butyl 4-(3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate as a
yellow solid.
LCMS (ESI, m/z): 285.2 [M+1-11+.
Step B
A solution of tert-butyl4-(3-hydroxy-2-oxopyrrolidin-l-yl)piperidine-1-
carboxylate
(2.0 g, 1.0 equiv) in 4N HC1 in dioxane (30 mL) was stirred for 1 hour at room
temperature.
The resulting mixture was concentrated to afford 1.8 g of crude 3-hydroxy-1-
(piperidin-4-
yl)pyrrolidin-2-one hydrochloride as a white solid that was carried forward
without further
purification. LCMS (ESI, m/z): 185.1 [M+1-11+.
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Intermediate 1-4: Synthesis of N-methy1-1-(5-(trifluoromethyl)thiazol-2-
yl)piperidin-4-
amine
CF3
CF3
A
Boc, NH ___
___________________________________________________________ HCIN
Boc,
HN
Step A
A solution of tert-butyl methyl(piperidin-4-yl)carbamate (214 mg, 0.99 mmol,
1.0
equiv), 2-bromo-5-(trifluoromethyl)thiazole (232 mg, 0.99 mmol, 1.0 equiv) and
K2CO3 (207
mg, 1.49 mmol, 1.5 equiv) in NMP (5 mL) was stirred for 2 hours at 80 C. Water
(20 mL)
was added and the resulting solution was extracted with 3 x 15 mL of ethyl
acetate. The
organic layers were combined, dried over magnesium sulfate, filtered, and
concentrated. The
crude product was applied onto a silica gel column eluting with ethyl
acetate/petroleum ether
(2/3) to afford 343 mg (94% yield) of tert-butyl methyl(1-(5-
(trifluoromethypthiazol-2-
yOpiperidin-4-yOcarbamate as a white solid. LCMS (ESI, m/z): 366.1 [M+Hr.
Step B
A solution of tert-butyl methyl(' -(5-(trifluoromethypthiazol-2-yOpiperidin-4-
yl)carbamate (343 mg, 0.94 mmol, 1.00 equiv) in 4N HC1 in dioxane (5 mL) was
stirred for 1
hour and then the mixture was concentrated to afford 275 mg (97% yield) of N-
methy1-1-(5-
(trifluoromethypthiazol-2-yOpiperidin-4-amine hydrochloride as a white solid.
LCMS (ESI,
m/z): 266.00 [M+H]+.
Intermediates I-5 ¨1-6 were synthesized according to the procedures described
for the
synthesis of N-methy1-1-(5-(trifluoromethypthiazol-2-yOpiperidin-4-amine
(Intermediate 1-4)
using appropriate building blocks and modified reaction conditions (such as
reagent ratio,
temperature, coupling conditions, and reaction time) as needed.
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Intermediate
Structure Analytical Data
No.
N
HCI I I
N
HN
1-5 LCMS
(ESI, m/z): 233.25 [M+1-11+
(N-methyl-1 -(5-
(trifluoromethyl)pyrimidin-2-
yl)azetidin-3-amine
hydrochloride
N,CF3
HCI X r
0\1 N
HN
1-6
LCMS (ESI, m/z): 261.1 [M+1-11+
N-methyl-1 -(5 -
(trifluoromethyl)pyrazin-2-
yl)piperidin-4-amine
hydrochloride
Example 1: Synthesis of (S)-2-(2-(6-oxo-5-(trifluoromethyl)-1,6-
dihydropyridazin-4-
ylamino)propoxy)-N-(1-(5-(trifluoromethyDpyrimidin-2-yDpiperidin-4-yDacetamide
iND--CF3
HCOI
Boc _OH A BocON
Ir"\N
H2N
0
0
F3CJLNH N
F3CAN'PMB I NI I
N HN 0 1\1'
I I I
_________________ HN N 0 1\1'
õ,s=OJLN,-)
Step A
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A solution of tert-butyl piperidin-4-ylcarbamate (2.00 g, 9.98 mmol, 1.0
equiv), 2-
chloro-5-(trifluoromethyl)pyrimidine (1.82 g, 9.99 mmol, 1.0 equiv), and K2CO3
(1.38 g,
9.99 mmol, 1.0 equiv) in NMP (50 mL) was stirred for 2 hours at 80 C. Water
(200 mL) was
added and the solids were collected by filtration to afford tert-butyl 1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-ylcarbamate (3.7 g, 96% yield, 90%
purity) as a
white solid. LCMS (ESI, m/z): 347.15 [M+1-11+.
Step B
A solution of tert-butyl 1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-
ylcarbamate
(2.31 g, 6.0 mmol, 1.0 equiv, 90% purity) in 4N HC1 in 1,4-dioxane (20 mL) was
stirred for 1
hour at room temperature. The solids were collected by filtration to afford 1-
(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-amine hydrochloride (1.27 g, 82%
yield) as a
white solid. LCMS (ESI, m/z): 247.20 [M+1-11+.
Step C
A solution of (S)-2-(2-((1-(4-methoxybenzy1)-6-oxo-5-(trifluoromethyl)-1,6-
dihydropyridazin-4-yl)amino)propoxy)acetic acid (200 mg, 0.48 mmol, 1.0 equiv,
50%
purity; Intermediate 1-2), DIEA (187 mg, 1.44 mmol, 3.0 equiv), HATU (183 mg,
0.48 mmol,
1.0 equiv), and 1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-amine
hydrochloride (119
mg, 0.48 mmol, 1.0 equiv) in DMF (2.0 mL) was stirred for 1 hour at room
temperature.
After concentration, the residue was applied onto a reverse phase column
eluting with
H20/CH3CN (31/69) to afford (S)-2-(2-(1-(4-methoxybenzy1)-6-oxo-5-
(trifluoromethyl)-1,6-
dihydropyridazin-4-ylamino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-
yl)acetamide (51 mg, 15% yield) as a yellow oil. LCMS (ESI, m/z): 644.20
[M+H1+.
Step D
To a solution of (S)-2-(2-(1-(4-methoxybenzy1)-6-oxo-5-(trifluoromethyl)-1,6-
dihydropyridazin-4-ylamino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-
yl)acetamide (49 mg, 0.076 mmol, 1.0 equiv) in TFA (1.00 mL) at 0 C was added
triflic acid
(0.10 mL) and the solution was maintained at that temperature for 1 hour. Ice
water (30 mL)
was added and the pH value of the solution was adjusted to pH 7 with saturated
aqueous
NaHCO3. The resulting solution was extracted with 3 x 60 mL of ethyl acetate.
The organic
layers were combined, dried over anhydrous sodium sulfate and concentrated
under vacuum.
The residue was applied onto a reverse phase column eluting with H20/CH3CN
(50/50) to
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afford (S)-2-(2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-
ylamino)propoxy)-N-(1-
(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide (14 mg, 35% yield)
as a white
solid. LCMS (ESI, m/z): 524.2 [M+H1+; 11-1NMR (300 MHz, DMSO-d6) 6 12.48 (s,
1H),
8.74 (s, 2H), 7.97 (s, 1H), 7.58 (d, J= 8.1 Hz, 1H), 6.46- 6.39 (m, 1H), 4.62
(d, J = 13.5 Hz,
2H), 4.22- 4.15 (m, 1H), 4.01 - 3.90 (m, 2H), 3.89 (s, 2H), 3.52 (d, J= 5.4
Hz, 2H), 3.16 (t,
J= 12.2 Hz, 2H), 1.80 (d, J= 9.3 Hz, 2H), 1.42- 1.30 (m, 2H), 1.18 (d, J= 6.6
Hz, 3H).
Example 2: Synthesis of (S)-N-methy1-2-(2-(6-oxo-5-(trifluoromethyl)-1,6-
dihydropyridazin-4-ylamino)propoxy)-N-(1-(5-(trifluoromethyppyrimidin-2-
y1)piperidin-4-ypacetamide
Boc
Boc HCI 0
1-114 F3CN-PMB
N-
I NI I
A 01 HN 0 1\1
)i-N\
CF3
CF3 CF3
0
F3C)LNH
I k
______________________ HN N 0 1\1"
Step A
A solution of tert-butyl 1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-
ylcarbamate
(2.31 g, 6.67 mmol, 1.00 equiv; Example 1, Step A) at 0 C in DMF was treated
with NaH
(800 mg, 20.0 mmol, 3.0 equiv, 60% dispersion in mineral oil). After 15
minutes
iodomethane (0.95 g, 6.67 mmol, 1.0 equiv) was added and the solution was
stirred for 1 hour
at room temperature. 50 mL of water was added and the solids were collected by
filtration to
afford tert-butylmethyl(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-
yl)carbamate (1.65
g, 63% yield) as a white solid. LCMS (ESI, m/z): 361.20 [M+1-11+.
Step B
A solution of tert-butyl methyl(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-
4-
yl)carbamate (1.65 g, 4.578 mmol, 1.00 equiv) in 4N HC1 in 1,4-dioxane (16 mL)
was stirred
for 1 h at room temperature. The solids were collected by filtration to afford
N-methy1-1-(5-
(trifluoromethyppyrimidin-2-yOpiperidin-4-amine hydrochloride (1.21 g, 96%
yield) as a
white solid. LCMS (ESI, m/z): 261.20 [M+1-11+.
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Step C
A solution of (S)-2-(2-((1-(4-methoxybenzy1)-6-oxo-5-(trifluoromethyl)-1,6-
dihydropyridazin-4-yl)amino)propoxy)acetic acid (200 mg, 0.48 mmol, 1.0 equiv;
Intermediate 1-2), N-methy1-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-
amine
hydrochloride (125 mg, 0.48 mmol, 1.0 equiv), DIEA (187 mg, 1.44 mmol, 3.0
equiv) and
HATU (183 mg, 0.48 mmol, 1.0 equiv) in DMF (2 mL) was stirred for 1 hour at
room
temperature. After concentration, the residue was applied onto a reverse phase
column eluting
with H20/CH3CN (26/74) to afford (S)-2-(2-(1-(4-methoxybenzy1)-6-oxo-5-
(trifluoromethyl)-1,6-dihydropyridazin-4-ylamino)propoxy)-N-methyl-N-(1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide (117 mg, 29% yield)
as a yellow
oil. LCMS (ESI, m/z): 658.25[M+Hr
Step D
A solution of (S)-2-(2-(1-(4-methoxybenzy1)-6-oxo-5-(trifluoromethyl)-1,6-
dihydropyridazin-4-ylamino)propoxy)-N-methyl-N-(1-(5-
(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-yl)acetamide (115 mg, 0.18 mmol, 1.0 equiv) in TFA (2.00 mL) at
0 C was
treated with triflic acid (0.20 mL) and maintained at that temperature for 20
min. Ice water
(30 mL) was added and the pH value of the solution was adjusted to pH 7 with
saturated
aqueous NaHCO3. The resulting solution was extracted with 3 x 100 mL of ethyl
acetate. The
organic layers were combined, dried over anhydrous sodium sulfate and
concentrated under
vacuum. The residue was applied onto a reverse phase column eluting with
H20/CH3CN
(42/58) to afford (S)-N-methy1-2-(2-(6-oxo-5-(trifluoromethyl)-1,6-
dihydropyridazin-4-
ylamino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-y1)piperidin-4-
y1)acetamide (18 mg,
19% yield) as a white solid. LCMS (ESI, m/z): 538.2 [M+H1+; 11-INMR (300 MHz,
DMSO-
d6) 6 12.22 (s, 1H), 8.65 (s, 2H), 7.89 (s, 1H), 6.75 - 6.50 (br, 1H), 4.86
(d, J= 12.6 Hz, 2H),
4.60 - 4.40 (rotamer A, m, 1H), 4.30 (s, 1H), 4.22 - 4.12 (m, 3H), 3.85 - 3.79
(rotamer B, m,
1H). 3.52 - 3.48 (m, 2H), 3.10 - 2.89 (m, 2H), 2.65 -2.72 (m, 3H), 1.80- 1.50
(m, 4H), 1.23
(d, J = 6.6 Hz, 3H).
Examples 3 - 5 were synthesized according to the procedures described for the
synthesis of (S)-N-methy1-2-(2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-
4-
ylamino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-y1)piperidin-4-
y1)acetamide (see
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Example 2) using appropriate building blocks and modified reaction conditions
(such as
reagent ratio, temperature, coupling conditions, and reaction time) as needed.
Example No. Structure Analytical Data
LCMS (ESI, m/z): 543.20 [M+H1+;
cF3
F3CNH NMR (300 MHz, DMSO-d6) 6 12.46
I NI
(s, 1H), 7.92 (s, 1H), 7.70 (t, J = 1.5
Hz, 1H), 6.79 ¨ 6.59 (m, 1H), 4.57 ¨
(S)-N-methyl-2-(2-((6-oxo-5- 4.42(m, 1H), 4.29 (s, 1H), 4.25 ¨ 4.15
3 (trifluoromethyl)-1,6- (m, 2H), 4.02 - 3.91 (m, 2H), 3.55
¨
dihydropyridazin-4- 3.48 (m, 2H), 3.27¨ 3.12(m, 2H), 2.68
yl)amino)propoxy)-N-(1-(5- (d, J = 8.7 Hz, 3H), 1.91 ¨ 1.62 (m,
(trifluoromethypthiazol-2- 3H), 1.61 ¨ 1.55 (m, 1H), 1.16 (d, J =
yl)piperidin-4-yl)acetamide 6.4 Hz, 3H).
F3cj(LNH LCMS (ESI, m/z): 538.20 [M+H1+;
NMR (300 MHz, DMSO-d6) 5 12.47
CF3
NY
(s, 1H), 8,47 (d, J = 1.8 Hz, 2H), 7.95
(s, 1H), 6.73 - 6.50(m, 1 H), 4.62 -
4 (S)-N-methyl-2-(2-(6-oxo-5- 4.58 (m, 3 H), 4.34 - 4.19(m, 3
H),
(trifluoromethyl)-1,6- 3.61 ¨3.54 (m, 2H), 3.10 ¨ 2.91 m, 2
dihydropyridazin-4- H), 2.68 (d, J= 9.3 Hz, 3H), 1.71 -
ylamino)propoxy)-N-(1-(5- 1.60 (m, 4H), 1.18 (d, J = 6.2 Hz,
3H).
(trifluoromethyl)pyrazin-2-
yl)piperidin-4-yl)acetamide
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Example No. Structure Analytical Data
F3C)LNH CF3
N
HNN
I I
I LCMS (ESI, m/z): 510.20; 1I-1NMR
o
N
(400 MHz, DMSO-d6) 6 12.48 (s, 1H),
8.71 (s, 2H), 7.95 (s, 1H), 6.80 - 6.71
((S)-N-methyl-2-(2-(6-oxo-5- (m, 1H), 5.34 ¨ 5.24 (m, 1H), 4.45 ¨
(trifluoromethyl)-1,6- 4.15 (m, 7H), 3.54 (d, J= 5.9 Hz,
2H),
dihydropyridazin-4- 2.96 (s, 3H), 1.17 (d, J= 6.5 Hz,
3H).
ylamino)propoxy)-N-(1-(5-
(trifluoromethyl)pyrimidin-2-
yl)azetidin-3-yl)acetamide
Example 6: Synthesis of (S)-N-(1-(5-cyanopyridin-2-Apiperidin-4-y1)-N-methyl-2-
(2-
06-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yDamino)propoxy)acetamide
N,
Boc_C/NHA Bocs rNN--"µ n--CN
____________________________________________________ \
0
0
F30,)L ,PMB F3CJL NH
HNN
HNN
_00¨\ CN D 0
c-- \.../(
5 Step A
A solution of tert-butyl methyl(piperidin-4-yl)carbamate (1.00 g, 4.666 mmol,
1.00
equiv), 6-chloronicotinonitrile (0.52 g, 3.733 mmol, 0.80 equiv) and K2CO3
(0.64 g, 4.666
mmol, 1.0 equiv) in NMP (50 mL) was stirred for 2 hours at 80 C. 150 mL of
water was
added and the solids were collected by filtration to afford tert-butyl (1-(5-
cyanopyridin-2-
yOpiperidin-4-y1)(methyl)carbamate (970 mg, 59% yield) as a white solid. LCMS:
[M+I-11+
317.10.
Step B
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A solution of tert-butyl (1-(5-cyanopyridin-2-yOpiperidin-4-
y1)(methyl)carbamate
(960 mg, 3.034 mmol, 1.00 equiv) in 4N HC1 in 1,4-dioxane (20 mL) was stirred
for 1 h at
room temperature. The solution was concentrated to afford 6-(4-
(methylamino)piperidin-1-
yl)nicotinonitrile hydrochloride (810 mg, 99% yield) as a yellow oil. LCMS:
[M+Hr 217.20.
Step C
A solution of (S)-2-(2-((1-(4-methoxybenzy1)-6-oxo-5-(trifluoromethyl)-1,6-
dihydropyridazin-4-yl)amino)propoxy)acetic acid (77 mg, 0.185 mmol, 1.00
equiv;
Intermediate 1-2), 6-(4-(methylamino)piperidin-1-yl)nicotinonitrile
hydrochloride (26 mg,
0.120 mmol, 0.65 equiv), DIEA (23 mg, 0.185 mmol, 1 equiv), and HATU (46 mg,
0.120
mmol, 0.65 equiv) in DMF (2 mL) was stirred for 1 hour. After concentration,
the residue
was applied onto a reverse phase column eluting with H20/CH3CN (37/63) to
afford (S)-N-
(1-(5-cyanopyridin-2-yl)piperidin-4-y1)-2-(2-((1-(4-methoxybenzy1)-6-oxo-5-
(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-N-methylacetamide
(51 mg,
43% yield) as a yellow oil. LCMS: [M-411+ 614.25.
Step D
To a solution of (S)-N-(1-(5-cyanopyridin-2-yOpiperidin-4-y1)-2-(2-41-(4-
methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-
y1)amino)propoxy)-N-
methylacetamide (50 mg, 0.081 mmol, 1.00 equiv) in TFA (1.00 mL) at 0 C was
added
triflic acid (0.10 mL) and the mixture was stirred for 1 hour at that
temperature. Ice water (30
mL) was added and the pH value of the solution was adjusted to 7 with
saturated aqueous
NaHCO3. The resulting solution was extracted with 3 x 60 mL of ethyl acetate.
The organic
layers were combined, dried over anhydrous sodium sulfate and concentrated
under vacuum.
The residue was applied onto a reverse phase column eluting with H20/CH3CN
(51/49) to
afford (S)-N-(1-(5-cyanopyridin-2-yl)piperidin-4-y1)-N-methy1-2-(2-((6-oxo-5-
(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)acetamide (15 mg,
36% yield) as
a white solid. LCMS: [M-411+ 494.20. 1FINMR (300 MHz, DMSO-d6) 6 12.48 (s,
1H), 8.48
(d, J = 3.0 Hz, 1H), 7.95 (s, 1H), 7.83 (dd, J = 9.3, 2.4 Hz, 1H), 6.97 (d, J=
9.1 Hz, 1H), 6.73
¨ 6.65 (m, 1H), 4.71 ¨ 4.50 (m, 2H), 4.33 (s, 1H), 4.15(s, 2H), 3.80 -3.75 (m,
1H), 3.60 -3.50
(m, 2H), 3.01 ¨2.88 (m, 2H), 2.67 (d, J= 9.6 Hz, 3H), 1.78 ¨ 1.52 (m, 4H),
1.18 (d, J = 6.4
Hz, 3H).
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Example 7: Synthesis of (S)-N-ethy1-2-(2-06-oxo-5-(trifluoromethyl)-1,6-
dihydropyridazin-4-y1)amino)propoxy)-N-(1-(5-(trifluoromethyppyrimidin-2-
yl)piperidin-4-ypacetamide
F3CLN,PMB F3CAN,PMB F3Cj=N_FMB
I I I I I rj HCI
HNN A
HN.*N 0 .1\rBoc B
HN.- 0 NH
OH
0
0
,pmg F3CJ.LNH
I NCF3 Irj
D HN
HN 0 0 N
0
Step A
A solution of (S)-2-(2-((1-(4-methoxybenzy1)-6-oxo-5-(trifluoromethyl)-1,6-
dihydropyridazin-4-yl)amino)propoxy)acetic acid (414 mg, 1.0 mmol, 1.0 equiv;
Intermediate 1-2), HATU (380 mg, 1.0 mmol, 1.0 equiv), DIEA (260 mg, 2 mmol,
2.00
equiv) and tert-butyl 4-(ethylamino)piperidine-1-carboxylate (230 mg, 1.0
mmol, 1.0 equiv)
in DMF (4 mL) was stirred for 1 hour at room temperature. The residue was
purified by
reverse phase chromatography eluting with H20/CH3CN to afford 200 mg (32%
yield) of
tert-butyl (S)-4-(N-ethy1-2-(2-((1-(4-methoxybenzy1)-6-oxo-5-(trifluoromethyl)-
1,6-
dihydropyridazin-4-y0amino)propoxy)acetamido)piperidine-1-carboxylate as a
yellow oil.
LCMS (ESI, m/z): 626.25 [M+Hl+.
Step B
A solution of tert-butyl (S)-4-(N-ethy1-2-(2-41-(4-methoxybenzy1)-6-oxo-5-
(trifluoromethyl)-1,6-dihydropyridazin-4-y1)amino)propoxy)acetamido)piperidine-
1-
carboxylate (200 mg, 0.32 mmol, 1.0 equiv) in 4N HC1 in dioxane (5 mL) was
stirred for 2
hours at room temperature. The solution was concentrated under vacuum to
afford 130 mg
(78% yield) of (S)-N-ethy1-2-(2-((1-(4-methoxybenzy1)-6-oxo-5-
(trifluoromethyl)-1,6-
dihydropyridazin-4-yl)amino)propoxy)-N-(piperidin-4-yl)acetamide hydrochloride
as a
yellow oil that was carried forward without further purification. LCMS (ESI,
m/z): 526.25
[M+H]+.
Step C
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A solution of (S)-N-ethy1-2-(2-((1-(4-methoxybenzy1)-6-oxo-5-(trifluoromethyl)-
1,6-
dihydropyridazin-4-y0amino)propoxy)-N-(piperidin-4-y0acetamide (130 mg, 0.25
mmol, 1.0
equiv), K2CO3 (104 mg, 0.75 mmol, 3.0 equiv), and 2-chloro-5-
(trifluoromethyl)pyrimidine
hydrochloride (46 mg, 0.25 mmol, 1.0 equiv) in DMF (5 mL) was stirred for 2
hours at room
.. temperature. Water was added and the resulting solution was extracted with
dichloromethane.
The organic layers were combined, dried over anhydrous sodium sulfate and
concentrated
under vacuum. The residue was purified by reverse phase chromatography eluting
with
H20/CH3CN to afford 140 mg (83% yield) of (S)-N-ethy1-2-(2-41-(4-
methoxybenzy1)-6-oxo-
5-(trifluoromethyl)-1,6-dihydropyridazin-4-y0amino)propoxy)-N-(1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)acetamide as a yellow solid.
LCMS (ESI,
m/z): 672.25 [M+H]+.
Step D
A solution of (S)-N-ethy1-2-(2-((1-(4-methoxybenzy1)-6-oxo-5-(trifluoromethyl)-
1,6-
dihydropyridazin-4-yl)amino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-
yl)acetamide (140 mg, 0.21 mmol, 1.00 equiv) in trifluoroacetic acid (3 mL) at
0 C was
treated with triflic acid (0.3mL) and maintained at that temperature for 1
hour. Water was
added and the pH value was adjusted to 6 with saturated aqueous Na2CO3
solution. The
resulting solution was extracted with dichloromethane. The organic layers were
dried over
anhydrous sodium sulfate and concentrated under vacuum. The crude residue was
purified by
reverse phase chromatography eluting with H20/CH3CN to afford 80 mg (69%
yield) of (S)-
N-ethy1-2-(2-46-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-
y0amino)propoxy)-N-(1-
(5-(trifluoromethyl)pyrimidin-2-y1)piperidin-4-y1)acetamide as a white solid.
LCMS (ESI,
m/z): 552.20 [M+H]+; 11-1NMR (DMSO-d6, 300 MHz) (512.47 (s, 1H), 8.69 (s, 2H),
7.93 (s,
1H), 6.75 ¨6.68 (m, 1H), 4.82 (d, J = 13.1 Hz, 2H), 4.27 (s, 1H), 4.18 (d, J =
3.5 Hz, 2H),
.. 3.80 ¨ 3.71 (m, 1H), 3.56 (d, J = 5.6 Hz, 2H), 3.15 (d, J = 7.3 Hz, 2H),
3.01 ¨2.89 (m, 2H),
1.78 ¨ 1.62 (m, 4H), 1.18 (t, J = 5.8 Hz, 3H), 1.12 ¨ 0.93 (m, 3H).
Example 8: Synthesis of (S)-N-methy1-2-01-(6-oxo-5-(trifluoromethyl)-1,6-
dihydropyridazin-4-ypazetidin-2-y1)methoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-
2-
y1)piperidin-4-ypacetamide
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0 0
0 F3CAN,PMB F3C
N,PMB
F3C N,PMB I I 01H HCI A
NI NI
C./NN C ciN N
D
=0 0
0
F3CA ,PMB 0
F3C
Y"
N
--0 0 0 ND--CF3
CF3
_____________________________ N_ /
D-
Step A
A solution of (S)-azetidin-2-ylmethanol hydrochloride (1.20 g, 9.71 mmol, 1.0
equiv),
TEA (2.80 mL), and 5-chloro-2-(4-methoxybenzy1)-4-(trifluoromethyl)pyridazin-
3(2H)-one
(3.20 g, 10.0 mmol, 1.03 equiv; Intermediate I-1) in ethanol (20 mL) was
stirred for 1 h at 60
C. After cooling to room temperature, the solution was concentrated under
vacuum. The
crude product was purified by reverse phase chromatography eluting with
H20/CH3CN to
afford 2.0 g (55% yield) of (S)-5-(2-(hydroxymethyl)azetidin-1-y1)-2-(4-
methoxybenzy1)-4-
(trifluoromethyl)pyridazin-3(2H)-one as a white solid. LCMS (ESI, m/z): 370.15
[M+H1+.
.. Step B
A solution of (S)-5-(2-(hydroxymethyl)azetidin-1-y1)-2-(4-methoxybenzy1)-4-
(trifluoromethyl)pyridazin-3(2H)-one (738 mg, 1.99 mmol, 1.0 equiv), tert-
butyl 2-
chloroacetate (604 mg, 4.01 mmol, 2.01 equiv), and NaH (60% dispersion in oil,
240 mg, 6.0
mmol, 3.0 equiv) in DMF (10 mL) was stirred for 2 hours at 0 C. After
concentration, the
residue was purified by C18 reverse phase chromatography eluting with
H20/CH3CN to
afford tert-butyl (S)-2-((1-(1-(4-methoxybenzy1)-6-oxo-5-(trifluoromethyl)-1,6-
dihydropyridazin-4-yl)azetidin-2-yl)methoxy)acetate 430 mg (44% yield) as a
yellow oil.
LCMS (ESI, m/z): 483.15 [M+H1+.
Step C
A solution of tert-butyl (S)-2-((1-(1-(4-methoxybenzy1)-6-oxo-5-
(trifluoromethyl)-
1,6-dihydropyridazin-4-y0azetidin-2-yOmethoxy)acetate (420 mg, 0.87 mmol, 1.0
equiv) in
TFA (5 mL) and DCM (5 mL) was stirred for 2 hours at room temperature and the
solution
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was concentrated to afford 490 mg (92% yield) of (S)-2-41-(1-(4-methoxybenzy1)-
6-oxo-5-
(trifluoromethyl)-1,6-dihydropyridazin-4-y0azetidin-2-yOmethoxy)acetic acid as
a brown oil.
LCMS (ESI, m/z): 428.10 [M+Hr.
Step D
A solution of (S)-2-((1-(1-(4-methoxybenzy1)-6-oxo-5-(trifluoromethyl)-1,6-
dihydropyridazin-4-y0azetidin-2-yOmethoxy)acetic acid (274 mg, 1.05 mmol, 1.0
equiv),
DIEA (408 mg, 3.16 mmol, 3.0 equiv), and HATU (600 mg, 1.58 mmol, 1.5 equiv)
in DMF
(5 mL) was stirred for 1 hour at room temperature. The residue was purified
directly by
reverse phase chromatography eluting with H20/CH3CN to give 533 mg of (S)-2-
((1-(1-(4-
.. methoxybenzy1)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-y1)azetidin-
2-
y1)methoxy)-N-methyl-N-(1-(5-(trifluoromethyl)pyrimidin-2-y1)piperidin-4-
y1)acetamide
(76% yield) as a colorless oil. LCMS (ESI, m/z): 670.20[M+H1t
Step E
A solution of (S)-2-((1-(1-(4-methoxybenzy1)-6-oxo-5-(trifluoromethyl)-1,6-
dihydropyridazin-4-yl)azetidin-2-yl)methoxy)-N-methyl-N-(1-(5-
(trifluoromethyl)pyrimidin-
2-yl)piperidin-4-yl)acetamide (520 mg, 0.76 mmol, 1.0 equiv) and
trifluoromethanesulfonic
acid (0.33 mL) in trifluoroacetic acid (3.3 mL) was stirred for 1 hour at room
temperature. 20
mL of water was added and the pH value of the solution was adjusted to 8 with
saturated
aqueous Na2CO3. The resulting solution was extracted with 3 x 15 mL of ethyl
acetate. The
organic layers were combined, dried over anhydrous sodium sulfate and
concentrated under
vacuum. The residue was purified by C18 reverse phase chromatography eluting
with
H20/CH3CN to afford 65 mg of (S)-N-methy1-2-((1-(6-oxo-5-(trifluoromethyl)-1,6-
dihydropyridazin-4-y1)azetidin-2-y1)methoxy)-N-(1-(5-
(trifluoromethyl)pyrimidin-2-
y1)piperidin-4-y1)acetamide (15%) as a white solid. LCMS (ESI, m/z): 550.15
[M+I-11+. 1I-I
NMR (400 MHz, DMSO-d6) 6 12.36 (d, J = 10.6 Hz, 1H), 8.69 (d, J = 0.9 Hz, 2H),
7.75 (s,
1H), 4.89 - 4.78 (m, 3H), 4.57 - 4.52 (m, 1H), 4.42 - 4.27 (m, 2H), 4.24 (s,
1H), 3.88 (dr,
1H), 3.77 (dd, J = 10.2, 4.5 Hz, 2H), 3.04- 2.92 (m, 2H), 2.67 (d, J = 16.7
Hz, 3H), 2.49 -
2.41 (m, 1H), 2.11 - 2.01 (m, 1H), 1.71 - 1.46 (m, 4H).
Example 9: Synthesis of (S)-2-(3-methoxy-2-46-oxo-5-(trifluoromethyl)-1,6-
dihydropyridazin-4-yl)amino)propoxy)-N-methyl-N-(1-(5-
(trifluoromethyppyrimidin-2-
y1)piperidin-4-ypacetamide
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0
0
,
F3C-LN,PMB F3CANPMB
NH2 HDI A
I I
HNN
HNN __________________________________________________
\.¨OH ON.
0 0
0¨\
0
0 F3C)( NH
I
F3C-L NH
HNN
HNN
C 0 N
0 \--0\_1(
OH
Step A
A solution of methyl (R)-2-amino-3-methoxypropan-1-ol hydrochloride (4.00 g,
28.3
mmol, 1.0 equiv), TEA (8.58 g, 84.8 mmol, 3.0 equiv), and 5-chloro-2-(4-
methoxybenzy1)-4-
(trifluoromethyl)pyridazin-3(2H)-one (9.00 g, 28.24 mmol, 1.0 equiv;
Intermediate I-1) in i-
PrOH (40 mL) was stirred for 2 hours at 60 C. The resulting mixture was
concentrated under
vacuum and the crude product was applied onto a silica gel column eluting with
ethyl
acetate/petroleum ether (7:3) to afford 10.5 g (96% yield) of (R)-5-((1-
hydroxy-3-
methoxypropan-2-yl)amino)-2-(4-methoxybenzy1)-4-(trifluoromethyl)pyridazin-
3(2H)-one as
a white solid. LCMS (ESI, m/z): 388.10[M+Hr
Step B
To a solution of (R)-5-((1-hydroxy-3-methoxypropan-2-y0amino)-2-(4-
methoxybenzyl)-4-(trifluoromethyppyridazin-3(2H)-one (2.0 g, 5.16 mmol, 1.0
equiv) in
DMF (40 mL) at 0 C was added NaH (60% dispersion in mineral oil, 207 mg, 5.16
mmol,
1.0 equiv) portionwise. The solution was stirred for 15 minutes and then tert-
butyl 2-
bromoacetate (2.01 g, 10.33 mmol, 2.0 equiv) was added to the resulting
solution. The
mixture was stirred for 1 hour at room temperature. 30 mL of water was added
and the
resulting solution was extracted with 3 x 50 mL of ethyl acetate. The organic
layers were
combined, dried over anhydrous sodium sulfate and concentrated under vacuum.
The crude
product was applied onto a silica gel column eluting with ethyl
acetate/petroleum ether (1:1)
to afford 300 mg (12% yield) of tert-butyl (S)-2-(3-methoxy-2-41-(4-
methoxybenzy1)-6-oxo-
5-(trifluoromethyl)-1,6-dihydropyridazin-4-y0amino)propoxy)acetate as a yellow
solid.
LCMS (ESI, m/z): 502.20 [M+Hr.
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Step C
A solution of tert-butyl (S)-2-(3-methoxy-2-((1-(4-methoxybenzy1)-6-oxo-5-
(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)acetate (240 mg,
0.48 mmol, 1.0
equiv) in trifluoroacetic acid / triflic acid (5:1, 2.4 mL) was stirred for 3
hours at room
temperature. Water (20 mL) was added and the pH value of the solution was
adjusted to 8
with saturated aqueous NaHCO3. The resulting solution was extracted with 3 x
50 mL of
dichloromethane. The organic layers were combined, dried over anhydrous sodium
sulfate
and concentrated. The crude product was applied onto a C18 reverse phase
column eluting
with H20/CH3CN (7:3) to afford 60 mg (39% yield) (S)-2-(3-methoxy-2-((6-oxo-5-
(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)acetic acid as a
yellow solid.
LCMS (ESI, m/z): 326.10 [M+H1+.
Step D
A solution of (S)-2-(3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-
dihydropyridazin-
4-yl)amino)propoxy)acetic acid (55 mg, 0.17 mmol, 1.0 equiv), N-methy1-1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-amine (48 mg, 0.19 mmol, 1.10
equiv), HATU
(71 mg, 0.19 mmol, 1.10 equiv), and DIEA (44 mg, 0.34 mmol, 2.0 equiv) in DMF
(1 mL)
was stirred for 2 hours at room temperature. 10 mL of water was added and the
resulting
solution was extracted with 2 x 50 mL of ethyl acetate. The organic layers
were combined
and dried over anhydrous sodium sulfate. After concentration, the crude
product was purified
by reverse phase chromatography eluting with H20/CH3CN (45:55) to afford 16 mg
(17%
yield) of (S)-2-(3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-
4-
yl)amino)propoxy)-N-methyl-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-
yl)acetamide as a white solid. LCMS (ESI, m/z): 568.30 [M+1-11+; 11-1 NMR
(DMSO-d6, 300
MHz) 6 12.48 (s, 1H), 8.68 (s, 2H), 7.94 (s, 1H), 6.70 ¨ 6.55 (m, 1H), 4.82
(d, J = 13.2 Hz,
2H), 4.53 ¨4.41 (m, 1H), 4.48 ¨ 4.29 (m, 2H), 4.18 (s, 1H), 3.58 (d, J = 5.8
Hz, 2H), 3.47 (d,
J = 5.6 Hz, 2H), 3.27 (s, 3H), 3.10 ¨ 2.90 (m, 2H), 2.65 (d, J = 8.9 Hz, 3H),
1.80¨ 1.61 (m,
4H).
Example 10: Synthesis of 5-((S)-1-((S)-1-(1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-y1)-2-oxopyrrolidin-3-yloxy)propan-2-ylamino)-4-
(trifluoromethyl)pyridazin-3(2H)-one (10A) and 5-((S)-1-((R)-1-(1-(5-
(trifluoromethyl)pyrimidin-2-y1)piperidin-4-y1)-2-oxopyrrolidin-3-yloxy)propan-
2-
ylamino)-4-(trifluoromethyl)pyridazin-3(211)-one (10B)
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NH2
CF 3 cF3 - HCI
HON 0 ,CH.HCI A ______________________________ HN Boc 0 0
0 c.)
/01).N c
0
H0:11
--C1N
0F3
0 0
0
F3CN,PMB F3C,)(NH F30
I
HN N HN
D HN
71)-CF3 CF3
0
10A 10B
Step A
A solution of 3-hydroxy-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride (600
mg,
2.72 mmol, 1.0 equiv; Intermediate 1-3), 2-chloro-5-
(trifluoromethyl)pyrimidine (496 mg,
2.72 mmol, 1.0 equiv), and K2CO3 (751 mg, 5.44 mmol, 2.0 equiv) in DMF (40 mL)
was
stirred for 2 hours at 60 C. Water (30 mL) was added and the solids were
collected by
filtration and dried in an oven under reduced pressure to give 550 mg (61%
yield) of 1-(1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-y1)-3-hydroxypyrrolidin-2-one as a
white solid.
LCMS (ESI, m/z): 331.1 [M+H1+.
Step B
A solution of 1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-y1)-3-
hydroxypyrrolidin-2-one (550 mg, 1.67 mmol, 1.00 equiv) in DMF (60 mL) at 0 C
was
treated with NaH (60% dispersion in oil, 200 mg, 4.99 mmol, 3.0 equiv)
portionwise. The
mixture was stirred for 15 min at 0 C. tert-Butyl (S)-4-methy1-1,2,3-
oxathiazolidine-3-
carboxylate 2,2-dioxide (593 mg, 2.5 mmol, 1.5 equiv) was then added
portionwise. After
stirring for 1 hour at that temperature, 30 mL of water was added. The
resulting solution was
extracted with 3 x 50 mL of ethyl acetate. The organic layers were combined
and washed
with 3 x 30 ml of brine. The organics were dried over anhydrous sodium sulfate
and
concentrated. The crude product was applied onto a silica gel column eluting
with ethyl
acetate/hexane (9:1) to afford 480 mg (59% yield) of tert-butyl (S)-1-(1-(1-(5-
(trifluoromethyppyrimidin-2-yOpiperidin-4-y1)-2-oxopyrrolidin-3-yloxy)propan-2-
ylcarbamate as a yellow solid. LCMS (ESI, m/z): 488.2 [M+1-11+.
Step C
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A solution of tert-butyl (S)-1-(1-(1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-y1)-
2-oxopyrrolidin-3-yloxy)propan-2-ylcarbamate (480 mg, 1.00 equiv) in 4N HC1 in
dioxane
(30 mL) was stirred for 1 hour at room temperature. The mixture was
concentrated to afford
420 mg of 3-((S)-2-aminopropoxy)-1-(1-(5-(trifluoromethyppyrimidin-2-
yOpiperidin-4-
yl)pyrrolidin-2-one hydrochloride as a yellow solid. LCMS (ESI, m/z): 388.2
[M+H1+.
Step D
A solution of 3-((5)-2-aminopropoxy)-1-(1-(5-(trifluoromethyppyrimidin-2-
yOpiperidin-4-yppyrrolidin-2-one hydrochloride (220 mg, 0.52 mmol, 1.0 equiv),
triethylamine (157 mg, 1.56 mmol, 3.0 equiv), and 5-chloro-2-[(4-
methoxyphenyOmethy11-4-
(trifluoromethyl)pyridazin-3-one (165 mg, 0.52 mmol, 1.00 equiv) in Et0H
(40mL) was
stirred for 2 hours at 60 C. After concentration, the crude product was
applied onto a silica
gel column eluting with ethyl acetate/petroleum ether (9:1) to afford 280 mg
(81% yield) of
5-((5)-1-(1-(1-(5-(trifluoromethyppyrimidin-2-yOpiperidin-4-y1)-2-
oxopyrrolidin-3-
yloxy)propan-2-ylamino)-2-(4-methoxybenzyl)-4-(trifluoromethyppyridazin-3(2H)-
one as a
yellow oil. LCMS (ESI, m/z): 670.2 [M+H1+.
Step E
A solution of 5-((5)-1-(1-(1-(5-(trifluoromethyppyrimidin-2-yOpiperidin-4-y1)-
2-
oxopyrrolidin-3-yloxy)propan-2-ylamino)-2-(4-methoxybenzyl)-4-
(trifluoromethyppyridazin-3(211)-one (280 mg, 0.42 mmol, 1.0 equiv) in TFA (15
mL) at 0
C was treated with triflic acid (1.50 mL). After stirring for 1 hour at 0 C,
the pH value of
the solution was adjusted to 8 with saturated aqueous sodium bicarbonate. The
resulting
solution was extracted with 3 x 70 mL of dichloromethane. The organic layers
were
combined, dried over anhydrous sodium sulfate, and concentrated. The crude
product was
purified by reverse phase chromatography and further purified by chiral prep-
HPLC
(Column: CHIRALPAK IA, 2*25cm, Sum; Mobile Phase A: Hex:DCM=3:1 w/10 mM NH3-
Me0H, Mobile Phase B: Et0H; Flow rate: 20 mL/min; 10% B for 14 min; 220/254
nm) to
afford the separated compounds. The stereochemistry was assigned based on an x-
ray crystal
structure of Example 10 Isomer B (10B).
Example 10 Isomer A (10A): 5-((5)-1-((5)-1-(1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-y1)-2-oxopyrrolidin-3-yloxy)propan-2-ylamino)-4-
(trifluoromethyl)pyridazin-
3(2H)-one (59 mg, 35%, white solid). LC-MS: (ESI, m/z): 550.2 [M+H1+; 1FINMR
(400
MHz, DMSO-d6) 6 12.47 (s, 1H), 8.70 (s, 2H), 7.95 (s, 1H), 6.39 ¨ 6.30 (m,
1H), 4.85 ¨ 4.82
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(m,2H), 4.18 ¨ 4.11 (m, 1H), 4.10 ¨ 4.04 (dt, J = 12.7, 6.8 Hz, 2H), 3.83 (dd,
J = 10.0, 6.5 Hz,
1H), 3.61 (dd, J = 10.1, 4.7 Hz, 1H), 3.25-3.14 (m, 1H), 3.19 ¨ 3.09 (m, 1H),
3.13-3.01 (m,
2H), 2.31 ¨2.19 (m, 1H), 1.79¨ 1.55 (m, 5H), 1.18 (d, J = 6.5 Hz, 3H). Chiral
HPLC:
CHIRALPAK IA-3, 4.6*50mm, 311m; detected at 254 nm; Mobile phase A:
Hex:DCM=3:1
w/ 0.1%DEA, Mobile phase B: Et0H, 15% Mobile phase B; Flow rate: 1 mL/min; tR
=
1.472 min.
Example 10 Isomer B (10B): 5 -((5)-1-((R)-1-(1-(5-(trifluoromethyl)pyrimidin-2-
yOpiperidin-4-y1)-2-oxopyrrolidin-3-yloxy)propan-2-ylamino)-4-
(trifluoromethyppyridazin-
3(2H)-one (92 mg, 54%, white solid). LC-MS: (ESI, m/z): 550.2 [M+H1+; NMR (400
MHz, DMSO-d6) 12.47 (s, 1H), 8.70 (s, 2H), 7.95 (s, 1H), 6.39 ¨ 6.30 (m, 1H),
4.84 ¨ 4.81
(m, 2H), 4.18-4.08 (m, 3H), 3.83 (dd, J = 10.0, 6.5 Hz, 1H), 3.61 (dd, J =
10.1, 4.7 Hz, 1H),
3.25-3.24 (m, 1H), 3.18¨ 3.11 (m, 1H), 3.10-2.98 (m, 2H), 2.31 ¨2.19 (m, 1H),
1.79-1.45
(m, 5H), 1.18 (d, J = 6.5 Hz, 3H). Chiral HPLC: CHIRALPAK IA-3, 4.6*50 mm,
31,tm;
detected at 254 nm; Mobile phase A: Hex:DCM=3:1 w/ 0.1%DEA, Mobile phase B:
Et0H,
15% Mobile phase B; Flow rate: 1 mL/min; tR = 2.209 min.
Example 11: Synthesis of 4-chloro-5-((S)-1-(2-oxo-1-(1-(5-
(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-yl)pyrrolidin-3-yloxy)propan-2-ylamino)pyridazin-3(2H)-one
NH2HCI
o CKJLNH
0 0 I I
HN 0
A solution of 3-((S)-2-aminopropoxy)-1-(1-(5-(trifluoromethyppyrimidin-2-
yl)piperidin-4-yl)pyrrolidin-2-one (60 mg, 0.16 mmol, 1.0 equiv; see Example
10, step C),
4,5-dichloropyridazin-3(2H)-one (38 mg, 0.23 mmol, 1.5 equiv), and TEA (83 mg,
0.82
mmol, 5.3 equiv) in n-BuOH (3 mL) was stirred for 15 hours at 100 C. The
residue was
purified by reverse phase column eluting with H20/CH3CN (60/40). The product
was further
purified by prep-HPLC to afford 6 mg (8% yield) of 4-chloro-5-((S)-1-(2-oxo-1-
(1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yloxy)propan-2-
ylamino)pyridazin-3(2H)-one as a white solid. LCMS (ESI, m/z): 516.20 [M+H1+;
NMR
(400 MHz, Methanol-d4) 6 8.55 (s, 2H), 7.96 (d, J= 9.9 Hz, 1H), 5.01 ¨ 4.91
(m, 2H), 4.24 ¨
4.06 (m, 3H), 4.00¨ 3.86 (m, 1H), 3.72 (dd, J= 9.7, 4.6 Hz, 1H), 3.41 ¨ 3.33
(m, 1H), 3.31-
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3.23 (m, 1H), 3.10 ¨ 2.97 (m, 2H), 2.42 ¨ 2.27 (m, 1H), 1.89¨ 1.87 (m, 1H),
1.85 ¨ 1.63 (m,
4H), 1.31 (d, J = 6.6 Hz, 3H).
Example 12: Synthesis of 4-bromo-5-4(25)-1-42-oxo-1-(1-(5-
(trifluoromethyppyrazin-2-
y1)piperidin-4-y1)pyrrolidin-3-yBoxy)propan-2-yl)amino)pyridazin-3(2H)-one
NH2 Hcl
o Br)-LNH
cr\N
___________________________________________ HN.. 0
cF3
--CF3
A solution of 3-((S)-2-aminopropoxy)-1-(1-(5-(trifluoromethyl)pyrazin-2-
yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride (90 mg, 0.212 mmol, 1.00
equiv; see
Example 13, Step C), 4,5-dibromopyridazin-3(2H)-one (54 mg, 0.213 mmol, 1.00
equiv), and
Et3N (65 mg, 0.637 mmol, 3.00 equiv) in n-butyl alcohol (2 mL) was stirred for
3 days at 100
.. C. The resulting solution was concentrated and purified by reverse phase
chromatography
eluting with H20/CH3CN (53/47) to afford impure desired product. The product
was further
purified by prep-HPLC to afford 11 mg (9% yield) of 4-bromo-5-(42S)-1-42-oxo-1-
(1-(5-
(trifluoromethyppyrazin-2-yOpiperidin-4-yOpyrrolidin-3-y0oxy)propan-2-
yl)amino)pyridazin-3(2H)-one as a white solid. LCMS (ESI, m/z): 560.10 [M+H1+;
11-1NMR
(300 MHz, DMSO-d6) 6 12.53 (s, 1H), 8.47 (s, 2H), 7.82 (s, 1H), 5.90 ¨ 5.79
(m, 1H), 4.65 ¨
4.45 (m, 2H), 4.20 ¨ 4.00 (m, 3H), 3.90 ¨ 3.78 (m, 1H), 3.62 ¨ 3.48 (m, 1H),
3.30 ¨ 2.90 (m,
4H), 2.30 ¨ 2.11 (m, 1H), 1.79¨ 1.51 (m, 5H), 1.15 (d, J= 6.5 Hz, 3H).
Example 13: 5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrazin-2-
yl)piperidin-4-
yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-
one
(13A) and 5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrazin-2-
yl)piperidin-4-
yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-
one
(13B)
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CF3 HN¨Boc
HCI
0 N \-0 0
A 0 HON
C
HOty
IC1F12
0
HCI 0
F3C I ,PMB
0
I
HN N
0
CF3
N
0 0
F3C F3C
I H
HN 0 HNN
õN___CN411¨CF3 F C. 3
13A 13B
Step A
A solution of 3-hydroxy-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride (717
mg,
3.26 mmol, 1.0 equiv; Intermediate 1-3), 2-chloro-5-(trifluoromethyl)pyrazine
(654 mg, 3.58
mmol, 1.1 equiv), and K2CO3(900 mg, 6.51 mmol, 2.0 equiv) in DMF (8 mL) was
stirred for
2 hours at 60 C. Water was added and the resulting solution was extracted
with 3 x 10 mL of
ethyl acetate. The organic layers were washed with 3 x 50 mL of brine, dried
over anhydrous
sodium sulfate and concentrated under vacuum. The crude product was applied
onto a silica
gel column and eluted with dichloromethane/methanol (97:3) to afford 702 mg
(65% yield)
of 3-hydroxy-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-2-
one as a
yellow solid. LCMS (ES, m/z): 331.15 [M+1-11+.
Step B
To a solution of methyl 3-hydroxy-1-(1-(5-(trifluoromethyl)pyrazin-2-
yl)piperidin-4-
yl)pyrrolidin-2-one (680 mg, 2.06 mmol, 1.0 equiv) in DMF (6 mL) at 0 C was
added NaH
(60% dispersion in oil, 82 mg, 2.06 mmol, 1.0 equiv) portionwise. The
resulting solution was
stirred for 15 minutes at that temperature and then tert-butyl (S)-4-methy1-
1,2,3-
oxathiazolidine-3-carboxylate 2,2-dioxide (537 mg, 2.27 mmol, 1.1 equiv) was
added to the
resulting solution. After stirring for 2 hours at 0 C, 5 mL of water was
added and the
mixture was concentrated under vacuum. The residue was applied onto a silica
gel column
eluting with ethyl acetate/petroleum ether (39:61) to afford 500 mg (50%
yield) of tert-butyl
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((2S)-1-((2-oxo-1-(1-(5-(trifluoromethyppyrazin-2-yOpiperidin-4-yOpyrrolidin-3-
y0oxy)propan-2-yOcarbamate as a yellow oil. LCMS (ES, m/z): 488.25[M+H1t
Step C
A solution of tert-butyl ((2S)-1-((2-oxo-1-(1-(5-(trifluoromethyppyrazin-2-
yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)carbamate (300 mg, 0.62
mmol, 1.0 equiv)
in 4N HC1 in dioxane (5 mL) was stirred for 1 hour at room temperature and
then
concentrated under vacuum to afford 200 mg (84% yield) of 3-((S)-2-
aminopropoxy)-1-(1-
(5-(trifluoromethyl)pyrazin-2-yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride
as a yellow
solid. LCMS (ES, m/z): 388.20[M+H1t
Step D
A solution of 3-((S)-2-aminopropoxy)-1-(1-(5-(trifluoromethyl)pyrazin-2-
yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride (150 mg, 0.39 mmol, 1.0
equiv),
triethylamine (78 mg, 0.77 mmol, 2.0 equiv), and 5-chloro-2-(4-methoxybenzy1)-
4-
(trifluoromethyl)pyridazin-3(2H)-one (136 mg, 0.43 mmol, 1.1 equiv;
Intermediate I-1) in
Et0H (5.00 mL) was stirred for 1 hour at 60 C. The resulting mixture was
concentrated and
applied onto a silica gel column eluting with ethyl acetate/petroleum ether
(85:15) to afford
160 mg (62% yield) of 2-(4-methoxybenzy1)-5-(42S)-1-42-oxo-1-(1-(5-
(trifluoromethyl)pyrazin-2-yOpiperidin-4-yOpyrrolidin-3-y0oxy)propan-2-
y0amino)-4-
(trifluoromethyl)pyridazin-3(2H)-one as white solid. (ES, m/z): 670.20 [M+H1+.
Step E
A solution of 2-(4-methoxybenzy1)-5-(42S)-1-((2-oxo-1-(1-(5-
(trifluoromethyl)pyrazin-2-yOpiperidin-4-yOpyrrolidin-3-y0oxy)propan-2-
y0amino)-4-
(trifluoromethyl)pyridazin-3(2H)-one (150 mg, 0.22 mmol, 1.0 equiv) in TFA
(3.00 mL) at -
10 C was treated with triflic acid (0.3 mL) and stirred for 1 hour at -10 C.
5 mL of ice water
was added and the pH value was adjusted to 8 with saturated aqueous Na2CO3.
The resulting
solution was extracted with 3 x 10 mL of ethyl acetate and the organics were
combined, dried
over anhydrous sodium sulfate and concentrated under vacuum. The crude product
was
purified by reverse phase chromatography to afford a mixture of isomers. The
mixture was
further purified by chiral prep-HPLC: (CHIRALPAK IG, 2.0*25cm, Sum; Mobile
Phase A:
Hex:DCM=3:1 w/10 mM NH3-Me0H, Mobile Phase B: Et0H; Flow rate: 16 mL/min; 50%
B for 19 min; 220/254 nm) to afford the desired isomers. The relative
stereochemistry of
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compounds was assigned by analogy to Example 10, based on the PARP7 potency of
the
more active diastereomer and in analogy to the Example 10B X-ray crystal
structure.
Example 13 Isomer A (13A): 5-(((S)-1-(((S)-2-oxo-1-(1-(5-
(trifluoromethyl)pyrazin-2-
yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-
(trifluoromethyl)pyridazin-
3(2H)-one (23 mg, 27% yield) as a white solid. LCMS (ESI, m/z): 550.20 [M+H1+;
NMR
(300 MHz, DMSO-d6) 6 12.45 (s, 1H), 8.47 (d, J = 3.1 Hz, 2H), 7.92 (s, 1H),
6.45 -6.32 (m,
1H), 4.59 (d, J = 13.6 Hz, 2H), 4.18 -4.07 (m,3H), 3.84 (dd, J = 10.0, 4.2 Hz,
1H), 3.60 (dd, J
= 10.0, 6.9 Hz, 1H), 3.25 - 3.19 (m, 1H), 3.18 - 3.04 (m, 3H), 2.25 -2.17 (m,
1H), 1.80 -
1.55 (m, 5H), 1.18 (d, J = 6.0 Hz, 3H). Chiral HPLC: (CHIRALPAK IG-3,
4.6*50mm, 3 um;
Hex:DCM=3:1 w/0.1%DEA : Et0H=80 : 20; 1.0 mL/min, tR = 2.423 min.)
Example 13 Isomer B (13B): 5-(((S)-1-(((R)-2-oxo-1-(1-(5-
(trifluoromethyl)pyrazin-2-
yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-
(trifluoromethyl)pyridazin-
3(2H)-one (45 mg, 53% yield) as a white solid. LCMS (ESI, m/z): 550.20 [M+H1+;
1H NMR
(300 MHz, DMSO-d6) 6 12.48 (s, 1H), 8.47 (d, J = 3.9 Hz, 2H), 7.95 (s, 1H),
6.46 - 6.32 (m,
1H), 4.59 (d, J = 13.4 Hz, 2H), 4.18 -4.07 (m,3H), 3.83 (dd, J = 10.0, 6.6 Hz,
1H), 3.60 (dd, J
= 10.0, 6.9 Hz, 1H), 3.25 -3.19 (m, 1H), 3.16 - 2.99 (m, 3H), 2.25 -2.17 (m,
1H), 1.81 -
1.56 (m, 5H), 1.17 (d, J = 6.4 Hz, 3H). Chiral HPLC: (CHIRALPAK IG-3,
4.6*50mm, 3 um;
Hex:DCM=3:1 w/0.1%DEA : Et0H=80 : 20; 1.0 mL/min, tR = 3.085 min.)
Example 14: Synthesis of 6-(4-((S)-2-oxo-3-((S)-2-46-oxo-5-(trifluoromethyl)-
1,6-
dihydropyridazin-4-yl)amino)propoxy)pyrrolidin-1-yl)piperidin-1-
yl)nicotinonitrile
(14A) and 6-(4-((R)-2-oxo-3-((S)-2-46-oxo-5-(trifluoromethyl)-1,6-
dihydropyridazin-4-
y1)amino)propoxy)pyrrolidin-1-y1)piperidin-1-yl)nicotinonitrile (14B)
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BockNH
HO ___________
HCI N¨( HO sl\IH NN¨( \N-0¨/ CN ¨.13 -
______________ / N
1\1
NH2
HCI 0
0 0 F3C.)LN-PMB
I I
C D
HN
0
0
0
ii
F3C F3C.ANH
NH I I
HN 0
HN 0
CN
CN
14B
14A
Step A
A solution of 3-hydroxy-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride (700
mg,
3.17 mmol, 1.0 equiv; Intermediate 1-3), 6-chloronicotinonitrile (440 mg, 3.18
mmol, 1.0
equiv), and K2CO3 (1.30 g, 9.41 mmol, 2.97 equiv) in DMF (5 mL) was stirred
for 2 hours at
50 C. The resulting solution was diluted with 10 mL of water. The solids were
collected by
filtration to afford 530 mg (58% yield) of 6-(4-(3-hydroxy-2-oxopyrrolidin-l-
yl)piperidin-l-
yl)nicotinonitrile as a brown solid. LCMS (ESI, m/z): 287.20 [M+1-11+.
Step B
To a solution of 6-(4-(3-hydroxy-2-oxopyrrolidin-1-yl)piperidin-1-
yl)nicotinonitrile
(286 mg, 0.99 mmol, 1.0 equiv) in DMF (5 mL) was added NaH (60% suspension in
mineral
oil, 133 mg, 3.33 mmol, 3.3 equiv) at 0 C and the solution was stirred for 15
minutes. tert-
Butyl (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (261 mg,
1.10 mmol,
1.10 equiv) was added and the solution was stirred for 2 hours at 0 C. Water
was added and
the resulting mixture was concentrated under vacuum. The crude product was
purified by
reverse phase chromatography eluting with H20/CH3CN (40/60) to afford 200 mg
(45%
yield) of tert-butyl 42S)-1-41-(1-(5-cyanopyridin-2-yOpiperidin-4-y1)-2-
oxopyrrolidin-3-
y0oxy)propan-2-yOcarbamate as a yellow oil. LCMS (ESI, m/z): 444.30 [M+1-11+.
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Step C
A solution of tert-butyl 42S)-1-41-(1-(5-cyanopyridin-2-y1) piperidin-4-y1)-2-
oxopyrrolidin-3-yl)oxy)propan-2-yl)carbamate (180 mg, 1.0 equiv) in 4N HC1 in
dioxane (5
mL) was stirred for 2 hours at room temperature. The resulting mixture was
concentrated
under vacuum to afford 120mg (78% yield) of 6-(4-(3-((S)-2-aminopropoxy)-2-
oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile hydrochloride as a white
solid. LCMS (ESI,
m/z): 344.15 [M+H]+.
Step D
A solution of 6-(4-(3-((S)-2-aminopropoxy)-2-oxopyrrolidin-1-yl)piperidin-1-
yl)nicotinonitrile hydrochloride (110 mg, 0.32 mmol, 1.0 equiv), 5-chloro-2-(4-
methoxybenzy1)-4-(trifluoromethyppyridazin-3(2H)-one (101 mg, 0.32 mmol, 1.0
equiv;
Intermediate I-1), and N-methyl morpholine (97 mg, 0.96 mmol, 3.0 equiv) in
MeCN (2 mL)
was stirred for 12 hours at 60 C. The mixture was concentrated under vacuum
and the
residue was applied onto a silica gel column eluting with ethyl
acetate/petroleum ether (9/1)
.. to afford 70 mg (23% yield) of 6-(4-(3-((S)-2-41-(4-methoxybenzy1)-6-oxo-5-
(trifluoromethyl)-1,6-dihydropyridazin-4-y1)amino)propoxy)-2-oxopyrrolidin-1-
y1)piperidin-
1-y1)nicotinonitrile as a white solid. LCMS (ESI, m/z): 626.25 [M+Hl+.
Step E
A solution of 6-(4-(3-((S)-2-((1-(4-methoxybenzy1)-6-oxo-5-(trifluoromethyl)-
1,6-
dihydropyridazin-4-yl)amino)propoxy)-2-oxopyrrolidin-1-y1)piperidin-1-
y1)nicotinonitrile
(40 mg, 0.064 mmol, 1.0 equiv) in TFA (3 mL) at 0 C was treated with
trifluoromethanesulfonic acid (0.3 mL) and stirred for 1 hour at that
temperature. 10 mL of
ice water was added and the pH value of the solution was adjusted to 5-6 with
saturated
aqueous Na2CO3. The resulting solution was extracted with 3 x 10 mL of ethyl
acetate. The
organic layers were combined, dried over anhydrous sodium sulfate and
concentrated. The
crude product was purified by reverse phase chromatography eluting with
H20/CH3CN
(60/40) to afford a mixture of isomers. The product was further purified by
chiral prep HPLC
with the following conditions: (CHIRALPAK IA, 2*25cm, Sum; mobile phase A:
Hex:Et0H=1:1 w/8 mmol/L NH3-Me0H, mobile phase B: Et0H; flow rate: 16 mL/min;
50%
B: for 18 min; 220/254 nm) to afford the separated isomers. The relative
stereochemistry of
compounds was assigned by analogy to Example 10, based on the PARP7 potency of
the
more active diastereomer and in analogy to the Example 10B X-ray crystal
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Example 14 Isomer A (14A): 6-(4-((S)-2-oxo-3-((S)-2-46-oxo-5-(trifluoromethyl)-
1,6-
dihydropyridazin-4-y0amino)propoxy)pyrrolidin-1-y1)piperidin-1-
y1)nicotinonitrile (11 mg,
33% yield) as a white solid. LCMS (ESI, m/z): 506.20 [M+H1+;11-1-NMR (Methanol-
d4, 400
MHz) 6 8.40 (s, 1H), 7.98 (s, 1H), 7.72 (dd, J= 9.1, 2.4 Hz, 1H), 6.90 (dd, J
= 9.2, 0.8 Hz,
1H), 4.64 (m, J= 13.5 Hz, 2H), 4.19- 4.10 (m, 3H), 3.99 (dd, J = 9.8, 3.8 Hz,
1H), 3.63 (dd, J
= 9.8, 6.8 Hz, 1H), 3.38 (dd, J = 9.7, 3.6 Hz, 1H), 3.29 ¨ 3.21 (m, 2H), 3.10
¨ 2.98 (m, 2H),
2.42 ¨2.29 (m, 1H), 2.42 ¨2.29 (m, 1H), 1.92¨ 1.79 (m, 1H), 1.78 ¨ 1.65 (m,
4H), 1.30 (d, J
= 6.6 Hz, 3H). Chiral HPLC: (CHIRALPAK IA-3, 4.6*50mm, 3um; Hex w/ 0.1%DEA :
Et0H = 50:50; Flow rate: 1 mL/min; tR = 2.167 min).
Example 14 Isomer B (14B): 6-(4-((R)-2-oxo-3-((S)-2-46-oxo-5-(trifluoromethyl)-
1,6-
dihydropyridazin-4-y0amino)propoxy)pyrrolidin-1-y1)piperidin-1-
y1)nicotinonitrile (14 mg,
43% yield) as a white solid. LCMS (ESI, m/z): 506.20 [M+1-11+; 1-1-1NMR (400
MHz,
Methanol-d4) 6 8.40 (dd, J= 2.4, 0.7 Hz, 1H), 8.00 (s, 1H), 7.72 (dd, J = 9.1,
2.4 Hz, 1H),
6.90 (dd, J= 9.2, 0.8 Hz, 1H), 4.64 (m, J= 13.5 Hz, 2H), 4.19- 4.10 (m, 3H),
3.99 (dd, J=
9.8, 3.8 Hz, 1H), 3.63 (dd, J = 9.8, 6.8 Hz, 1H), 3.38 (dd, J= 9.7, 3.6 Hz,
1H), 3.29¨ 3.21
(m, 2H), 3.10 ¨ 2.98 (m, 2H), 2.42 ¨ 2.29 (m, 1H), 1.92¨ 1.79 (m, 1H), 1.78¨
1.65 (m, 4H),
1.30 (d, J= 6.6 Hz, 3H). Chiral HPLC: (CHIRALPAK IA-3, 4.6*50mm, 3um; Hex w/
0.1%DEA : Et0H = 50:50; Flow rate: 1 mL/min; tR = 3.159 min).
Example 15: Synthesis of 5-4(S)-1-4(S)-1-(1-(5-(difluoromethyppyrimidin-2-
.. yl)piperidin-4-y1)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-
(trifluoromethyl)pyridazin-3(2H)-one (15A) and 5-4(S)-1-4(R)-1-(1-(5-
(difluoromethyppyrimidin-2-y1)piperidin-4-y1)-2-oxopyrrolidin-3-ypoxy)propan-2-
y1)amino)-4-(trifluoromethyppyridazin-3(2H)-one (15B)
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HN¨Boc
0 0
HOH A 0 0
N NH HON¨iN¨CN--C C=\¨/ CF2H
N¨1
N--)--"CF2H
NH2 HCI 0
00 F3C -PMB
E
N
HN 0
N
jNr--CF2H = 0 4 CF2H
0 0
F3c
yUNH F3C,..),..I Ni"
HN N 0 HNN0
_PD--CF2H
/
15A 15B
Step A
A solution of 3-hydroxy-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride (1.20
g,
5.437 mmol, 1.99 equiv; Intermediate 1-3), 2-chloro-5-
(difluoromethyl)pyrimidine (450 mg,
2.735 mmol, 1.00 equiv) and K2CO3 (2.27 g, 16.43 mmol, 6.01 equiv) in DMF (15
mL) was
stirred for 15 hours at 80 C. After filtration, the filtrate was concentrated
under vacuum and
the crude product was applied onto a reverse phase column eluting with
H20/CH3CN (1:1) to
afford 450 mg (46% yield) of 1-(1-(5-(difluoromethyl)pyrimidin-2-yl)piperidin-
4-y1)-3-
hydroxypyrrolidin-2-one as a yellow solid. LCMS (ESI, m/z): 313.20 [M+Hr.
Step B
To a solution of 1-(1-(5-(difluoromethyl)pyrimidin-2-yl)piperidin-4-y1)-3-
hydroxypyrrolidin-2-one (150 mg, 0.480 mmol, 1.00 equiv) in DMF (10 mL) was
added NaH
(120 mg, 3.00 mmol, 6.25 equiv, 60% dispersion in mineral oil) at 0 C and
stirred for 10
min. To the solution was added tert-butyl (S)-4-methyl-1,2,3-oxathiazolidine-3-
carboxylate
2,2-dioxide (177 mg, 0.746 mmol, 1.55 equiv) at 0 C. The resulting solution
was stirred for 2
hours at room temperature. The reaction was then quenched by the addition of
0.2 mL of 20%
aqueous sodium carbonate. The solution was concentrated and the crude product
was applied
onto a reverse phase column eluting with H20/CH3OH (40/60) to afford 224 mg
(50% yield)
of tert-butyl ((2S)-1-((1-(1-(5-(difluoromethyl)pyrimidin-2-yl)piperidin-4-y1)-
2-
oxopyrrolidin-3-yl)oxy)propan-2-yl)carbamate as an orange solid. LCMS (ESI,
m/z): 470.15
[M+H]+.
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Step C
A solution of tert-butyl 42S)-1-41-(1-(5-(difluoromethyppyrimidin-2-
yOpiperidin-4-
y1)-2-oxopyrrolidin-3-y0oxy)propan-2-yOcarbamate (250 mg, 0.532 mmol, 1.00
equiv) in 4N
HC1 in dioxane (5 mL) was stirred for 2 hours at room temperature. The
resulting mixture
was concentrated to afford 220 mg (71% yield) of 3-((S)-2-aminopropoxy)-1-(1-
(5-
(difluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride
as an orange
solid. LCMS (ESI, m/z): 370.15[M+H1t
Step D
A solution of 3-[(2S)-2-aminopropoxy1-1-[1-[5-(difluoromethyl)pyrimidin-2-
yllpiperidin-4-yllpyrrolidin-2-one hydrochloride (220 mg, 0.542 mmol, 1.00
equiv), 5-
chloro-2-[(4-methoxyphenyOmethy11-4-(trifluoromethyppyridazin-3-one (189 mg,
0.593
mmol, 1.09 equiv) and TEA (180 mg, 1.779 mmol, 3.28 equiv) in Et0H (5 mL) was
stirred
for 3 hours at 60 C. The mixture was concentrated and diluted with 100 mL of
ethyl acetate
and washed with 2 x 20 mL of saturated aqueous ammonium chloride. The aqueous
layers
.. were combined and extracted with 2 x 50 mL of ethyl acetate. The organics
were combined,
dried over anhydrous sodium sulfate and concentrated. The residue was applied
onto a silica
gel column eluting with 100% ethyl acetate to afford 107 mg (30% yield) of 5-
(42S)-1-41-
(1-(5-(difluoromethyppyrimidin-2-yOpiperidin-4-y1)-2-oxopyrrolidin-3-
y0oxy)propan-2-
y0amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one as a
yellow solid.
LCMS (ESI, m/z): 652.50 [M+H1+.
Step E
A solution of 5-(42S)-1-41-(1-(5-(difluoromethyppyrimidin-2-yOpiperidin-4-y1)-
2-
oxopyrrolidin-3-y0oxy)propan-2-y0amino)-2-(4-methoxybenzyl)-4-
(trifluoromethyl)pyridazin-3(2H)-one (100 mg, 0.153 mmol, 1.00 equiv) in
.. trifluoromethanesulfonic acid / TFA = 1:10 (1.5 mL) was stirred for 2 hours
at room
temperature. The resulting solution was diluted with 15 mL of H20. The pH
value of the
solution was adjusted to 7-8 with 20% aqueous sodium carbonate. The resulting
solution was
extracted with 2 x 20 mL of ethyl acetate. The organic layers were combined,
dried over
anhydrous sodium sulfate and concentrated. The crude product was purified by
reverse phase
chromatography eluting with H20/CH3CN. The product was further purified by
chiral prep-
HPLC (CHIRAL ART Cellulose-SB, 2*25cm, Sum; Mobile Phase A: Hex w/ 8mmo1/L NH3-
Me0H, Mobile Phase B: Et0H; Flow rate: 20 mL/min; Gradient: 50% B for 16 min;
220/254
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nm). The relative stereochemistry of compounds was assigned by analogy to
Example 10,
based on the PARP7 potency of the more active diastereomer and in analogy to
the Example
10B X-ray crystal structure.
Example 15 Isomer A (15A): 5-(((S)-1-(((S)-1-(1-(5-(difluoromethyl)pyrimidin-2-
yOpiperidin-4-y1)-2-oxopyrrolidin-3-y0oxy)propan-2-y0amino)-4-
(trifluoromethyppyridazin-3(2H)-one (16 mg, 32% yield, off-white solid). LCMS
(ESI, m/z):
532.25 [M+H1+; NMR (400 MHz, DMSO-d6) 6 12.44 (s, 1H), 8.54 (s, 2H), 7.91
(s, 1H),
6.96 (t, J= 55.5 Hz, 1H), 6.41 - 6.32 (m, 1H), 4.86- 4.75 (m, 2H), 4.21 -4.14
(m, 1H), 4.08
-4.04 (m, 2H), 3.83 (dd, J = 10.0, 4.3 Hz, 1H), 3.59 (dd, J= 10.1, 7.0 Hz,
1H), 3.25 -3.19
(m, 1H), 3.15 -3.08 (m, 1H), 3.02- 2.95 (m, 2H), 2.25 -2.16 (m, 1H), 1.73 -
1.48 (m, 5H),
1.16 (d, J= 6.5 Hz, 3H). Chiral HPLC: CHIRAL Cellulose-SB, 0.46*10cm, 3um; Hex
w/0.1% DEA : Et0H = 50:50; Flow rate: 1.0 mL/min; rT = 2.642 min.
Example 15 Isomer B (15B): 5-4(5)-1-4(R)-1-(1-(5-(difluoromethyppyrimidin-2-
yOpiperidin-4-y1)-2-oxopyrrolidin-3-y0oxy)propan-2-y0amino)-4-
(trifluoromethyl)pyridazin-3(2H)-one (25 mg, 50% yield, off-white solid). LCMS
(ESI, m/z):
532.20 [M+H1+; NMR (400 MHz, DMSO-d6) 6 12.46 (s, 1H), 8.54 (s, 2H), 7.94
(s, 1H),
6.96 (t, J= 55.5 Hz, 1H), 6.41 - 6.32 (m, 1H), 4.86 - 4.75 (m, 2H), 4.21 -4.14
(m, 1H), 4.08
-4.03 (m, 2H), 3.83 (dd, J = 10.0, 4.3 Hz, 1H), 3.59 (dd, J= 10.1, 7.0 Hz,
1H), 3.25 -3.20
(m, 1H), 3.15 -3.09 (m, 1H), 3.03 -2.95 (m, 2H), 2.25 -2.17 (m, 1H), 1.73 -
1.66 (m, 1H),
1.61 - 1.48 (m, 4H), 1.17 (d, J= 6.5 Hz, 3H). Chiral HPLC: CHIRAL Cellulose-
SB,
0.46*10cm, 3um; Hex w/0.1% DEA : Et0H = 50:50; Flow rate: 1.0 mL/min; rT =
4.415 min.
Example 16: Synthesis of 5-4(S)-1-4(R)-1-(1-(5-chloropyrimidin-2-yl)piperidin-
4-y1)-2-
oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyppyridazin-3(2H)-
one
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,Boc
HCI
4CI A
,aCI
________________________________________ HOI-ar) ___________________ N
HO
0
CI
/11
N
01)Nj
,Boc
HN oj 0
HCI 0
H2N
.E7
0 0
F3CN,PMB
I F3C-)L NH
I
HN N G
HNN
N- N-
_CN4N)--CI
Step A
A solution of (R)-2-(2,2-dimethy1-5-oxo-1,3-dioxolan-4-yl)acetaldehyde (3.47
g,
21.941 mmol, 1.00 equiv), tert-butyl 4-aminopiperidine-1-carboxylate (6.40 g,
31.955 mmol,
1.46 equiv), and acetic acid (2.64 g, 43.962 mmol, 2.00 equiv) in DCM (200 mL)
was stirred
for 15 minutes. NaBH(Ac0)3 (14.00 g, 66.042 mmol, 3.01 equiv) was added and
the solution
was stirred for another 2 hours at room temperature. 300 mL of saturated
aqueous NaHCO3
was added. The layers were separated and the aqueous layer was extracted with
3 x 200 mL
of dichloromethane. The organic layers were combined, dried over anhydrous
sodium sulfate
and concentrated under vacuum. The crude product was applied onto a silica gel
column
eluting with ethyl acetate/petroleum ether (75/25) to afford 2.9 g (46% yield)
of tert-butyl
(R)-4-(3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate as a yellow
solid. LCMS
(ESI, m/z): 285.15 [M+1-11+.
Step B
A solution of tert-butyl (R)-4-(3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-
carboxylate (2.90 g, 10.2 mmol, 1.00 equiv) in 1,4-dioxane (10 mL) and 4N HC1
in dioxane
(30 mL) was stirred for 15 hours at room temperature. The solution was
concentrated to
afford 2.2 g (98% yield) of (R)-3-hydroxy-1-(piperidin-4-yl)pyrrolidin-2-one
hydrochloride
as a yellow solid. LCMS (ESI, m/z): 185.15 [M+1-11+.
Step C
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A solution of (R)-3-hydroxy-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride
(700
mg, 3.172 mmol, 1.00 equiv), K2CO3 (1310 mg, 9.479 mmol, 2.99 equiv) and 2,5-
dichloropyrimidine (492 mg, 3.303 mmol, 1.04 equiv) in DMF (5 mL) was stirred
for 4 hours
at 80 C. 25 mL of water was added and the resulting solution was extracted
with 3 x 20 mL
.. dichloromethane. The organic layers were combined, dried over anhydrous
sodium sulfate,
filtered and concentrated under vacuum. The crude product was applied onto a
silica gel
column eluting with dichloromethane/Me0H (10:1) to afford 750 mg (80% yield)
of (R)-1-
(1-(5-chloropyrimidin-2-yl)piperidin-4-y1)-3-hydroxypyrrolidin-2-one as a
light yellow solid.
LCMS (ESI, m/z): 297.05 [M+Hr.
.. Step D
To a solution of (R)-1-(1-(5-chloropyrimidin-2-yl)piperidin-4-y1)-3-
hydroxypyrrolidin-2-one (350 mg, 1.179 mmol, 1.00 equiv) in DMF (6 mL) at 0 C
was
added NaH (60% dispersion in mineral oil, 236 mg, 5.901 mmol, 5 equiv)
portionwise. To
the solution was added tert-butyl (S)-4-methyl-1,2,3-oxathiazolidine-3-
carboxylate 2,2-
.. dioxide (420 mg, 1.770 mmol, 1.50 equiv). The resulting solution was
allowed to warm to
room temperature. 0.5 mL of water was added and the solvent was removed in
vacuo. The
crude product was purified by reverse phase chromatography eluting with
H20/CH3OH (7/3)
to afford 490 mg (82% yield) of tert-butyl ((S)-1-4(R)-1-(1-(5-chloropyrimidin-
2-
yOpiperidin-4-y1)-2-oxopyrrolidin-3-y0oxy)propan-2-yOcarbamate as a light
yellow solid.
LCMS (ESI, m/z): 454.15[M+Hr
Step E
A solution of tert-butyl ((S)-1-4(R)-1-(1-(5-chloropyrimidin-2-yOpiperidin-4-
y1)-2-
oxopyrrolidin-3-y0oxy)propan-2-yOcarbamate (490 mg, 1.079 mmol, 1.00 equiv) in
1,4-
dioxane (10.00 mL) and 4N HC1 in dioxane (5.00 mL) was stirred for 2 hours at
room
.. temperature. The resulting mixture was concentrated to afford 420 mg (90%
yield) of (R)-3-
((S)-2-aminopropoxy)-1-(1-(5-chloropyrimidin-2-yOpiperidin-4-yOpyrrolidin-2-
one
hydrochloride as alight yellow solid. LCMS (ESI, m/z): 354.15[M+Hr
Step F
A solution of (R)-3-((S)-2-aminopropoxy)-1-(1-(5-chloropyrimidin-2-yOpiperidin-
4-
.. yl)pyrrolidin-2-one hydrochloride (210 mg, 0.538 mmol, 1.00 equiv), TEA
(190 mg, 1.878
mmol, 3.49 equiv) and 5-chloro-2-[(4-methoxyphenyOmethy11-4-
(trifluoromethyppyridazin-
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3-one (205 mg, 0.643 mmol, 1.20 equiv) in Et0H (5 mL) was stirred for 4 hours
at 50 C.
The mixture was concentrated, diluted with 60 mL of ethyl acetate, and washed
with 2 x 20
mL of saturated aqueous NH4C1. The layers were separated and the aqueous layer
was
extracted with 2 x 50 mL of ethyl acetate. The organic layers were combined,
dried over
.. anhydrous sodium sulfate and concentrated. The residue was applied onto a
silica gel column
eluting with ethyl acetate/petroleum ether (3/1) to afford 240 mg (70% yield)
of 5-(((S)-1-
(((R)-1-(1-(5-chloropyrimidin-2-yOpiperidin-4-y1)-2-oxopyrrolidin-3-
y0oxy)propan-2-
y0amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one as a white
solid.
LCMS (ESI, m/z): 652.50 [M+Hr.
.. Step G
A solution of 5-4(S)-1-4(R)-1-(1-(5-chloropyrimidin-2-yOpiperidin-4-y1)-2-
oxopyrrolidin-3-y0oxy)propan-2-y0amino)-2-(4-methoxybenzyl)-4-
(trifluoromethyl)pyridazin-3(2H)-one (230 mg, 0.362 mmol, 1.00 equiv) in
trifluoromethanesulfonic acid / TFA=1:10 (2.50 mL) was stirred for 2 hour at
room
temperature. 15 mL of water was added and the pH value of the solution was
adjusted to 7-8
with 20% aqueous sodium bicarbonate. The solution was extracted with 3 x 20 mL
of ethyl
acetate. The organic layers were combined, dried over anhydrous sodium sulfate
and
concentrated. The crude product was purified by reverse phase chromatography
eluting with
H20/CH3CN to afford 99 mg of 5-(((S)-1-(((R)-1-(1-(5-chloropyrimidin-2-
yl)piperidin-4-y1)-
2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-
one.
LCMS (ESI, m/z): 516.15 [M+H1+;11-1NMR (400 MHz, DMSO-d6) 6 12.47 (s, 1H),
8.42 (s,
2H), 7.95 (s, 1H), 6.36 - 6.33 (m, 1H), 4.70 - 4.67 (m, 2H), 4.18 - 4.02 (m,
3H), 3.83 (dd, J
= 10.0, 6.6 Hz, 1H), 3.61 (dd, J= 10.0, 4.7 Hz, 1H), 3.34 - 3.21 (m, 1H), 3.14
- 3.11 (m,
1H), 2.98 - 2.92 (m, 2H), 2.25 - 2.23 (m, 1H), 1.74- 1.69 (m, 1H), 1.60- 1.51
(m, 4H), 1.17
(d, J= 6.5 Hz, 3H).
Example 17: Synthesis of 6-(4-((S)-3-((S)-3-methoxy-2-46-oxo-5-
(trifluoromethyl)-1,6-
dihydropyridazin-4-y1)amino)propoxy)-2-oxopyrrolidin-1-y1)piperidin-1-
y1)nicotinonitrile (17A) and 6-(4-((R)-3-((S)-3-methoxy-2-46-oxo-5-
(trifluoromethyl)-
1,6-dihydropyridazin-4-y1)amino)propoxy)-2-oxopyrrolidin-1-y1)piperidin-1-
.. yl)nicotinonitrile (17B)
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N¨Boc
"t0
0
HON,A
A
N¨CN¨CD¨CN
/ N
CN
¨0 NH2
HCI 0
F3CNõPMB
I I
HN N
0
_040¨
N CN
'ON
)r
NCN
0
0
F3CNH F3C
I N
N HN 0
HN 0 0
XCN
sN--/
17A 17B
Step A
To a solution of 6-(4-(3-hydroxy-2-oxopyrrolidin-1-yl)piperidin-1-
yl)nicotinonitrile
(300 mg, 1.048 mmol, 1.00 equiv; Example 14, Step A) in DMF (5 mL) was added
NaH (126
mg, 5.239 mmol, 5 equiv) at 0 C. The solution was stirred for 10 min at 0 C
and then tert-
butyl (S)-4-(methoxymethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide
(336 mg, 1.26
mmol, 1.2 equiv) was added. The solution was stirred for another 1 hour at 0
C. 20 mL of
methanol was added and the solution was concentrated. The crude product was
purified by
C18 reverse phase chromatography eluting with water/ACN (30/70) to afford 121
mg (24%
yield) of tert-butyl 42S)-1-41-(1-(5-cyanopyridin-2-yOpiperidin-4-y1)-2-
oxopyrrolidin-3-
y0oxy)-3-methoxypropan-2-yOcarbamate as a yellow solid. LCMS (ESI, m/z):
474.25
[M+H]+.
Step B
A solution of tert-butyl ((2S)-1-((1-(1-(5-cyanopyridin-2-yOpiperidin-4-y1)-2-
oxopyrrolidin-3-yl)oxy)-3-methoxypropan-2-yl)carbamate (121 mg, 0.256 mmol,
1.00 equiv)
in 4N HC1 in dioxane (8 mL) was stirred for 1.5 hours at room temperature. The
mixture was
concentrated under vacuum to afford 89 mg (93% yield) of 6-(4-(3-((S)-2-amino-
3-
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methoxypropoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile
hydrochloride as a
yellow oil. LCMS (ESI, m/z): 374.10 [M+Hr.
Step C
A solution of 5-chloro-2-(4-methoxybenzy1)-4-(trifluoromethyppyridazin-3(2H)-
one
(61 mg, 0.191 mmol, 1.00 equiv; Intermediate I-I), 6-(4-(3-((S)-2-amino-3-
methoxypropoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile
hydrochloride (71 mg,
0.191 mmol, 1.0 equiv) and TEA (58 mg, 0.574 mmol, 3.0 equiv) in ethanol (4.00
mL) was
stirred for 4 hours at 70 C in an oil bath. The mixture was concentrated under
vacuum and
the crude product was applied onto a silica gel column eluting with ethyl
acetate/petroleum
ether (10:1) to afford 60 mg (48% yield) of 6-(4-(3-((S)-3-methoxy-2-41-(4-
methoxybenzy1)-
6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-y1)amino)propoxy)-2-
oxopyrrolidin-1-
y1)piperidin-1-y1)nicotinonitrile as a yellow oil. LCMS (ESI, m/z): 656.20
[M+Hr.
Step D
A solution of 6-(4-(3-((S)-3-methoxy-2-((1-(4-methoxybenzy1)-6-oxo-5-
(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-2-oxopyrrolidin-1-
y1)piperidin-
1-y1)nicotinonitrile (54 mg, 0.082 mmol, 1.00 equiv) in TFA (2 mL) at 0 C was
treated with
triflic acid (0.2 mL) and stirred for 30 min at the same temperature. 10 mL of
ice water was
added and the pH value of the solution was adjusted to 8 with 40% aqueous
sodium
hydroxide. The resulting solution was extracted with 3 x 20 mL of ethyl
acetate. The organic
layers were combined, dried over magnesium sulfate, filtered, and concentrated
under
vacuum. The crude product was purified by reverse phase chromatography eluting
with water
/ ACN (60/40) to afford a mixture of isomers. The diastereomers were separated
by chiral
prep-HPLC with the following conditions: CHIRALPAK IF, 2*25cm, Sum; Mobile
Phase A:
Hex w/ 8mM NH3-Me0H, Mobile Phase B: Et0H; Flow rate: 20 mL/min; Gradient: 50%
B
for 22 min; 220/254 nm.) The relative stereochemistry of compounds was
assigned by
analogy to Example 10, based on the PARP7 potency of the more active
diastereomer and in
analogy to the Example 10B X-ray crystal structure.
Example 17 Isomer A (17A): 6-(4-((S)-3-((S)-3-methoxy-2-46-oxo-5-
(trifluoromethyl)-1,6-
dihydropyridazin-4-y0amino)propoxy)-2-oxopyrrolidin-1-y1)piperidin-1-
y1)nicotinonitrile
(5.3 mg, 12% yield, white solid). LCMS (ESI, m/z): 536.20[M+H1+; 1FINMR (400
MHz,
DMSO-d6) 6 12.48 (s, 1H), 8.47 (s, 1H), 7.93 (s, 1H), 7.83 (d, J= 9.1Hz, 1H),
6.96 (d, J=
9.2 Hz, 1H), 6.33 ¨ 6.28 (m, 1H), 4.58 ¨4.50 (m, 2H), 4.33 ¨ 4.26 (m, 1H),
4.09 ¨ 4.01 (m,
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2H), 3.92¨ 3.87 (m, 1H), 3.69¨ 3.63 (m, 1H), 3.48 (d, J= 5.7 Hz, 2H), 3.28 ¨
3.27 (m, 3H),
3.23 ¨3.19 (m, 1H), 3.15 ¨3.08 (m, 1H), 3.03 ¨ 2.95 (m, 2H), 2.27 ¨2.19 (m,
1H), 1.73 ¨
1.48 (m, 5H). Chiral HPLC: CHIRALPAK IF-3, 4.6*50mm, 3 pm; Hex w/ 0.1% DEA :
Et0H = 50:50; Flow rate:1 mL/min; rT = 2.405 min.
Example 17 Isomer B (17B): 6-(4-((R)-3-((S)-3-methoxy-2-46-oxo-5-
(trifluoromethyl)-1,6-
dihydropyridazin-4-y0amino)propoxy)-2-oxopyrrolidin-1-y1)piperidin-1-
y1)nicotinonitrile (9
mg, 20% yield, white solid). LCMS (ESI, m/z): 536.20 [M+H1+; 1-1-1NMR (400
MHz,
DMSO-d6) 6 12.50 (s, 1H), 8.47 (s, 1H), 7.96 (s, 1H), 7.83 (d, J= 9.1 Hz, 1H),
6.96 (d, J =
9.0 Hz, 1H), 6.33 ¨ 6.28 (m, 1H), 4.58-4.50 (m, 2H), 4.33-4.26 (m, 1H), 4.11 ¨
4.01 (m, 2H),
3.92-3.87 (m, 1H), 3.69-3.63 (m, 1H), 3.49 (d, J = 5.3 Hz, 2H), 3.29-3.26 (m,
3H),3.23-3.19
(m, 1H), 3.15-3.08(m,1H) , 3.03-2.94(m, 2H), 2.27-2.18 (m, 1H), 1.73 -1.48 (m,
5H). Chiral
HPLC: CHIRALPAK IF-3, 4.6*50mm, 3 pm; Hex w/ 0.1% DEA : Et0H = 50:50; Flow
rate:1 mL/min; rT = 3.678 min.
Example 18 was synthesized according to the procedures described for the
synthesis
of 6-(4-((S)-3-((S)-3-methoxy-2-46-oxo-5-(trifluoromethyl)-1,6-
dihydropyridazin-4-
y0amino)propoxy)-2-oxopyrrolidin-1-y1)piperidin-1-y1)nicotinonitrile and 6-(4-
((R)-3-((S)-3-
methoxy-2-46-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-y0amino)propoxy)-2-
oxopyrrolidin-1-yOpiperidin-1-yOnicotinonitrile (see Example 17) using
appropriate building
blocks and modified reaction conditions (such as reagent ratio, temperature,
coupling
conditions, and reaction time) as needed. The relative stereochemistry of
compounds was
assigned by analogy to Example 10, based on the PARP7 potency of the more
active
diastereomer and in analogy to the Example 10B X-ray crystal structure.
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Example No. Structure Analytical Data
LCMS (ESI, m/z): 580.20 [M+H1+;
NMR (400 MHz, DMSO-d6) 6 12.48
(s, 1H), 8.46 (d, J = 4.2 Hz, 2H), 7.93
F3c
)OH 0, 1H), 6.41-6.29 (m, 1H), 4.62-4.55
HN 0
r_Ny_cF3 (m, 2H), 4.34-4.27 (m, 1H), 4.11-4.03
/
(m, 2H), 3.90 (dd, J= 10.2, 4.7 Hz,
5-(((S)-1-methoxy-3-(((S)-2-
1H), 3.66 (dd, J= 10.2, 6.5 Hz, 1H),
oxo-1-(1-(5-
18A 3.48 (d, J = 5.5 Hz, 2H), 3.31-3.30(m,
(trifluoromethyl)pyrazin-2-
3H), 3.28-3.21 (m, 2H), 3.09-3.04 (m,
yl)piperidin-4-yl)pyrrolidin-3-
2H), 2.29 ¨ 2.17 (m, 1H), 1.75 ¨ 1.54
yl)oxy)propan-2-yl)amino)-4-
(m, 5H); Chiral HPLC: CHIRALPAK
(trifluoromethyl)pyridazin-
IF-3, 4.6*50mm, 3nm; Hex w/
3(2H)-one
0.1%DEA : Et0H = 50:50; Flow rate:
1 mL/min; rT = 1.858 min.
LCMS (ESI, m/z): 580.20 [M+H1+; 11-1
NMR (400 MHz, DMSO-d6) 6 12.50
(s, 1H), 8.49¨ 8.43 (d, J = 4.0 Hz,
0
2H), 7.96 (s, 1H), 6.31-6.23 (m, 1H),
HN 0 4.61-4.54 (m, 2H), 4.33-4.28 (m, 1H),
4.14-4.03 (m, 2H), 3.90 (dd, J= 10.2,
5-(((S)-1-methoxy-3-(((R)-2-
4.7 Hz, 1H), 3.66 (dd, J = 10.2, 6.5
oxo-1-(1-(5-
18B Hz, 1H), 3.49 (d, J = 5.3 Hz, 2H),
(trifluoromethyl)pyrazin-2-
3.28-3.27 (m, 3H),3.26-3.21 (m, 2H),
yl)piperidin-4-yl)pyrrolidin-3-
3.15-3.02 (m, 2H), 2.25-2.18 (m, 1H),
yl)oxy)propan-2-yl)amino)-4-
1.78-1.56 (m, 5H); Chiral HPLC:
(trifluoromethyl)pyridazin-
CHIRALPAK IF-3, 4.6*50mm, 3nm;
3(2H)-one
Hex w/ 0.1%DEA : Et0H = 50:50;
Flow rate: 1 mL/min; rT = 2.577 min.
Example 19: Synthesis of 5-4(S)-1-methoxy-3-4(S)-2-oxo-1-(1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-y1)pyrrolidin-3-yDoxy)propan-2-
yDamino)-
4-(trifluoromethyl)pyridazin-3(2H)-one (19A) and 5-(((S)-1-methoxy-3-(((R)-2-
oxo-1-(1-
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(5-(trifluoromethyppyrimidin-2-Apiperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-
yl)amino)-4-(trifluoromethyppyridazin-3(2H)-one (19B)
0 HN-Boc
HO o
A \"* .c--04
CF3
N 3
0
F30N-PMB
NH2 HCI I NI
\
HN 0
CF3
0 0
F3C)L
I r F3C1
HNN HNN
\µµ"c_--0
dNNN
0F3 -\\ 0F3
19A 19B
Step A
To a solution of 3-hydroxy-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-
yl)pyrrolidin-2-one (500 mg, 1.51 mmol, 1.00 equiv) in DMF (5 mL) at 0 C was
added NaH
(60% dispersion in mineral oil, 121mg, 3.02 mmol, 2.0 equiv). After stirring
at that
temperature for 15 minutes, a solution of tert-butyl (S)-4-(methoxymethyl)-
1,2,3-
oxathiazolidine-3-carboxylate 2,2-dioxide (605 mg 2.26 mmol, 1.50 equiv) in
DMF (3 mL) at
.. 0 C was added dropwise. The resulting solution was stirred for 2 h at 0 C.
50 mL of water
was added and the solution was extracted with 3 x 50 mL of Et0Ac. The organic
layers were
combined, washed with 50 mL of brine, dried over anhydrous sodium sulfate and
concentrated under vacuum. The crude product was applied onto a silica gel
column eluting
with Et0Ac / petroleum ether (11:9) to afford 500 mg (64% yield) of tert-butyl
((2S)-1-
methoxy-3-((2-oxo-1-(1-(5-(trifluoromethyppyrimidin-2-yOpiperidin-4-
yOpyrrolidin-3-
y0oxy)propan-2-yOcarbamate as a brown oil. LCMS (ESI, m/z): 518.20 [M+1-11+
Step B
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A solution of tert-butyl ((2S)-1-methoxy-3-((2-oxo-1-(1-(5-
(trifluoromethyppyrimidin-2-yOpiperidin-4-yOpyrrolidin-3-y0oxy)propan-2-
yOcarbamate
(500 mg, 0.97 mmol, 1.00 equiv) in 4N HC1 in 1,4-dioxane (4 mL) was stirred
for 1 h at room
temperature. After concentration, the crude product was purified by C18
reverse phase
chromatography eluting with H20/CH3CN (1:1) to afford 260 mg (65% yield) of 3-
((S)-2-
amino-3-methoxypropoxy)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-
yl)pyrrolidin-
2-one as a yellow solid. LCMS (ESI, m/z): 418.20 [M+1-11+.
Step C
A solution of 3-((S)-2-amino-3-methoxypropoxy)-1-(1-(5-
(trifluoromethyl)pyrimidin-
2-yl)piperidin-4-yl)pyrrolidin-2-one (250 mg, 0.60 mmol, 1.00 equiv), 5-chloro-
2-(4-
methoxybenzy1)-4-(trifluoromethyppyridazin-3(2H)-one (286 mg, 0.90 mmol, 1.50
equiv;
Intermediate I-1), and N-methyl morpholine (91 mg, 0.90 mmol, 1.50 equiv) in
CH3CN (4
mL) was stirred for 1 h at 60 C. The solution was diluted with 50 ml of water
and extracted
with 3 x 50 mL of Et0Ac. The organic layers were combined, washed with 50 mL
of brine,
dried over anhydrous sodium sulfate and concentrated under vacuum. The residue
was
applied onto a silica gel column eluting with Et0Ac /petroleum ether (7:13) to
afford 100 mg
(24% yield) of 5-(((2S)-1-methoxy-3-((2-oxo-1-(1-(5-(trifluoromethyppyrimidin-
2-
yOpiperidin-4-yOpyrrolidin-3-y0oxy)propan-2-y0amino)-2-(4-methoxybenzyl)-4-
(trifluoromethyl)pyridazin-3(2H)-one as a yellow solid. LCMS (ESI, m/z):
700.20[M+H1+
Step D
A solution of 5-(((2S)-1-methoxy-3-((2-oxo-1-(1-(5-(trifluoromethyppyrimidin-2-
yOpiperidin-4-yOpyrrolidin-3-y0oxy)propan-2-y0amino)-2-(4-methoxybenzyl)-4-
(trifluoromethyl)pyridazin-3(2H)-one (90 mg, 0.13 mmol, 1.00 equiv) in TFA
(1.00 mL) and
triflic acid (0.20 mL) was stirred for 1 h at room temperature. The residue
was diluted with
20 ml of water and the pH was adjusted to 7-8 with saturated aqueous Na2CO3
soluiton. The
resulting solution was extracted with 3 x 20 mL of Et0Ac. The organic layers
were
combined, washed with 20 mL of brine, dried over anhydrous sodium sulfate and
concentrated under vacuum. The crude product was purified by C18 reverse phase
column
eluting with H20 / CH3CN (16:29). The product was further purified by chiral
prep-HPLC
(CHIRALPAK IA, 2*25cm, Sum; Mobile Phase A: Hex (8mmo1/L NH3-Me0H), Mobile
Phase B: Et0H; Flow rate: 18 mL/min; 50% B for 20 min; 220/254 nm). The
relative
stereochemistry of compounds was assigned by analogy to Example 10, based on
the PARP7
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potency of the more active diastereomer and in analogy to the Example 10B X-
ray crystal
structure.
Example 19 Isomer A (19A): 5-(((S)-1-methoxy-3-(((S)-2-oxo-1-(1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-
yl)amino)-4-
(trifluoromethyl)pyridazin-3(2H)-one (20.8 mg, 28%yield, white solid). LCMS
(ESI, m/z):
580.20 [M+H1+; NMR (400 MHz, DMSO-d6) 6 12.48 (s, 1H), 8.69 (s, 2H), 7.93
(s, 1H),
6.37-6.30 (m, 1H), 4.88-4.74 (m, 2H), 4.35-4.24 (m, 1H), 4.14¨ 4.03 (m, 2H),
3.90 (dd,
J=10.0 Hz, 3.6Hz, 1H), 3.70-3.61 (m, 1H), 3.51-3.44 (m, 2H), 3.29-3.25 (m,
3H), 3.23-3.17
(m, 1H), 3.17 ¨2.97 (m, 3H) , 2.26 ¨ 2.18 (m, 1H), 1.78-1.49 (m, 5H); Chiral
HPLC:
CHIRALPAK IA-3, 4.6*50mm, 3p,m; Hex: Et0H = 50:50; Flow rate = 1.3 mL/min; rT
=
1.33 min.
Example 19 Isomer B (19B): 5-4(S)-1-methoxy-3-4(R)-2-oxo-1-(1-(5-
(trifluoromethyppyrimidin-2-yOpiperidin-4-yOpyrrolidin-3-y0oxy)propan-2-
y0amino)-4-
(trifluoromethyl)pyridazin-3(2H)-one (25.0 mg, 34%yield, white solid). LCMS
(ESI, m/z):
580.20 [M+H1+. NMR (400 MHz, DMSO-d6) 6 12.49 (s, 1H), 8.69 (s, 2H), 7.96
(s, 1H),
6.32 ¨ 6.24 (m, 1H), 4.86-4.77 (m, 2H), 4.35-4.24 (m, 1H), 4.15 ¨4.00 (m, 2H),
3.90 (dd,
J=10.0 Hz, 3.6 Hz, 1H), 3.71-3.63 (m, 1H), 3.52-3.45 (m, 2H), 3.28-3.27 (m,
3H) 3.24-3.21
(m, 1H), 3.18-2.97 (m, 3H), 2.31 ¨2.19 (m, 1H), 1.77-1.49 (m, 5H). Chiral
HPLC:
CHIRALPAK IA-3, 4.6*50mm, 3p,m; Hex: Et0H = 50:50; Flow rate = 1.3 mL/min; rT
=
2.91 min
Example 20: Synthesis of 5-(((S)-1-(((S)-2-oxo-l-(1-(5-
(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-
(trifluoromethyl)pyridazin-
3(2H)-one (20A) and 5-4(S)-1-4(R)-2-oxo-1-(1-(5-(trifluoromethyppyrimidin-2-
y1)piperidin-4-y1)pyrrolidin-3-ypoxy)p ropan-2-yl)oxy)-4-
(trifluoromethyl)pyrid azin-
.. 3(2H)-one (20B)
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HO Ts
A
N N
0
01HP OH F3CN,PMB
I
C--O 0 0
CF3
CF3
-\\
0 0
F3CY" F3C
AN 'N
_______________ "µ"0 ,s,"c_o 0
CF3
N¨/
20A 20B
Step A
A solution of 3-hydroxy-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-
yl)pyrrolidin-2-one (500 mg, 1.51 mmol, 1.00 equiv), 4-methylbenzenesulfonyl
chloride (864
.. mg, 4.53 mmol, 2.99 equiv), and TEA (612 mg, 6.06 mmol, 4.00 equiv) in DCM
(15 mL)
was stirred for 4 hours at 25 C. The resulting solution was diluted with 50
mL of water. The
layers were separated and the aqueous layer was extracted with 3 x 50 mL of
dichloromethane. The organic layers were combined, dried over anhydrous sodium
sulfate,
filtered and concentrated under vacuum to afford 500 mg (68% yield) of 2-oxo-1-
(1-(5-
.. (trifluoromethyppyrimidin-2-yOpiperidin-4-yOpyrrolidin-3-y1 4-
methylbenzenesulfonate as a
brown solid. LCMS (ESI, m/z): 485.20 [M+H1+.
Step B
A solution of (2S)-2-((tetrahydro-2H-pyran-2-y0oxy)propan-1-ol (264 mg, 1.65
mmol, 2.00 equiv) in DMF (4 mL) at 0 C was treated with NaH (60% dispersion
in mineral
.. oil, 67 mg, 1.65 mmol, 2.00 equiv) in DMF (4 mL) and stirred at that
temperature for 15
minutes. 2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-
yl)pyrrolidin-3-y1 4-
methylbenzenesulfonate (400 mg, 0.83 mmol, 1.00 equiv) was added and the
solution was
stirred for 2 hours at room temperature. 20 mL of saturated aqueous NH4C1 and
ethyl acetate
were added. The layers were separated and the aqueous layer was extracted with
Et0Ac (3 x
.. 50 mL). The organic layers were combined, washed with 5 mL brine, dried
over anhydrous
sodium sulfate and concentrated under vacuum to afford 450 mg of 3-((2S)-2-
((tetrahydro-
2H-pyran-2-y0oxy)propoxy)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-
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yl)pyrrolidin-2-one as a brown oil that was carried on without further
purification. LCMS
(ESI, m/z): 473.0 [M+H]+.
Step C
A solution of 3-42S)-2-((tetrahydro-2H-pyran-2-y0oxy)propoxy)-1-(1-(5-
.. (trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (900 mg,
1.91mmol, 1.00
equiv) in 4N HC1 in dioxane (6 mL) was stirred for 1 hour at room temperature.
The resulting
mixture was concentrated and the residue was applied onto a reverse phase
column eluting
with H20/CH3CN (1:2) to afford 250 mg (34% yield) of 3-((S)-2-hydroxypropoxy)-
1-(1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one as a yellow
solid. LCMS
(ESI, m/z): 389.10 [M+I-11+.
Step D
A solution of 3-((S)-2-hydroxypropoxy)-1-(1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-yl)pyrrolidin-2-one (75 mg, 0.16 mmol, 1.00 equiv), 5-chloro-2-
(4-
methoxybenzy1)-4-(trifluoromethyppyridazin-3(2H)-one (184 mg, 0.58 mmol, 3.64
equiv;
Intermediate I-1) and potassium tert-butoxide (65 mg, 0.58 mmol, 3.65 equiv)
in DCM (3.00
mL) was stirred for 15 hours at room temperature. The resulting solution was
diluted with 50
mL of DCM and washed with 50 ml H20 and 50 mL of brine. The mixture was dried
over
anhydrous sodium sulfate and concentrated. The crude product was applied onto
a silica gel
column eluting with Et0Ac/Petroleum ether (7/3) to afford 70 mg (66% yield) of
2-(4-
methoxybenzy1)-5-(42S)-1-((2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-
yOpiperidin-4-
yOpyrrolidin-3-y0oxy)propan-2-y0oxy)-4-(trifluoromethyppyridazin-3(2H)-one as
a
colorless oil. LCMS (ESI, m/z): 671.20 [M+1-11+.
Step E
A solution of 2-(4-methoxybenzy1)-5-(42S)-1-((2-oxo-1-(1-(5-
(trifluoromethyppyrimidin-2-yOpiperidin-4-yOpyrrolidin-3-y0oxy)propan-2-y0oxy)-
4-
(trifluoromethyppyridazin-3(2H)-one (65 mg, 0.10 mmol, 1.00 equiv) in TFA (1
mL) and
triflic acid (0.20 mL) was stirred for 1 hour at room temperature. The
solution was diluted
with water and adjusted to pH 7-8 with saturated aqueous Na2CO3. After
concentration, the
crude product was purified by C18 reverse phase chromatography eluting with
H20/CH3CN
(52:48). The product was further purified by Chiral-Prep-HPLC with following
conditions:
(CHIRALPAK IA, 2*25cm,5 p.m; mobile phase A: Hex w/8mM NH3-Me0H, mobile phase
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B: Et0H; Flow rate:20 mL/min; 50% B for 15 min; 220/254 nm.) The relative
stereochemistry of compounds was assigned by analogy to Example 10, based on
the PARP7
potency of the more active diastereomer and in analogy to the Example 10A X-
ray crystal
structure.
Example 20 Isomer A (20A): 5-(((S)-1-(((S)-2-oxo-1-(1-(5-
(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-
(trifluoromethyl)pyridazin-3(2H)-
one (13 mg, 24% yield, white solid). LCMS (ESI, m/z): 551.20 [M+Hr; 11-1 NMR
(400 MHz,
DMSO-d6) 6 13.22 (s, 1H), 8.69 (s, 2H), 8.28 (s, 1H), 5.22 ¨ 5.12 (m, 1H),
4.86-4.76 (m, 2H),
4.11 ¨3.94 (m, 3H), 3.65 ¨3.58 (m, 1H), 3.24 ¨ 3.16 (m, 1H), 3.15 ¨3.09 (m,
1H), 3.08 ¨
2.97 (m, 2H), 2.24 ¨ 2.13 (m, 1H), 1.68¨ 1.47 (m, 5H), 1.27 (d, J= 6.2 Hz,
3H). Chiral
HPLC: CHIRALPAK IA-3, 4.6*50mm, 3 p.m; Hex w/0.1% DEA : Et0H = 50:50; Flow
rate=1.0 mL/min; rT = 1.981 min.
Example 20 Isomer B (20B): 5-4(S)-1-4(R)-2-oxo-1-(1-(5-
(trifluoromethyppyrimidin-2-
yOpiperidin-4-yOpyrrolidin-3-y0oxy)propan-2-y0oxy)-4-(trifluoromethyppyridazin-
3(2H)-
one (17.5 mg, 33%yield, white solid). LCMS (ESI, m/z): 551.20 [M+Hl+ . 1H NMR
(400
MHz, DMSO-d6) 6: 13.22 (s, 1H), 8.69 (s, 2H), 8.30 (s, 1H), 5.22-5.12 (m, 1H),
4.86-4.77
(m, 2H), 4.11-3.99 (m, 2H), 3.89-3.82 (m, 1H), 3.77-3.70 (m, 1H), 3.25-3.17
(m, 1H), 3.16-
3.08 (m, 1H), 3.07-2.98 (m, 2H), 2.28-2.17 (m, 1H), 1.75 ¨ 1.47 (m, 5H), 1.27
(d, J = 6.2 Hz,
3H). Chiral HPLC: CHIRALPAK IA-3, 4.6*50mm, 3 p.m; Hex w/0.1%DEA : Et0H =
50:50;
Flow rate=1.0 mL/min; rT = 2.695 min.
The compounds of Examples 21-33B were synthesized analogously to the compounds
described in Example 1-20.
Ex. No. Name Structure
Analytical
Data
4-(trifluoromethyl)-5- F F F
(trifluoromethyl)pyn
HN, z
N
midin-2-yl)piperidin-
LCMS (ESI,
21
m/z): 536.20
4-yl)pyrrolidin-3-
[M+H]+
yl)oxy)propan-2-
yl)amino)pyridazin-
3(2H)-one
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5-(((S)-1-(((S)-1-(1-
(5-
(difluoromethyl)pyra
N,
zin-2-yl)piperidin-4- F 0 r NH
LCMS (ESI,
22A* y1)-2-oxopyrrolidin- F
m/z): 532.2
N [M+H]+
3-yl)oxy)propan-2-
F F
yl)amino)-4-
(trifluoromethyl)pyri
dazin-3(2H)-one
-
(5-
(difluoromethyl)pyra
zin-2-yl)piperidin-4- F 0 N,NH
LCMS (ESI,
22B* y1)-2-oxopyrrolidin-
m/z): 532.2
N
3-yl)oxy)propan-2- FF [M+H]+
yl)amino)-4-
(trifluoromethyl)pyri
dazin-3(2H)-one
4-bromo-5-(((S)-1-
(((S)-2-oxo-1-(1-(5-
(trifluoromethyl)pyri 0
midin-2-yl)piperidin- Br)-L
LCMS (ESI,
23 0 ri
m/z): 561.1
4-yl)pyrrolidin-3-
[M+H]+
F NI
yl)oxy)propan-2-
yl)oxy)pyridazin-
3(2H)-one
5-(((S)-1-(((R)-1-(1-
(5-bromopyrimidin N.
-
0 -NH
2-yl)piperidin-4-y1)-
LCMS (ESI,
24
m/z): 561.1
2-oxopyrrolidin-3- N
+
yl)oxy)propan-2-
F F [M+H]
yl)amino)-4-
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(trifluoromethyl)pyri
dazin-3(2H)-one
(S)-N-methyl-2-(2-
((6-oxo-5-
(trifluoromethyl)-1,6-
dihydropyridazin-4-
25 yl)oxy)propoxy)-N- HNN (p F
LCMS (ESI,
3NN
m/z): 539.2
(1-(5- 0 0 i [M+H]+
(trifluoromethyl)pyri
F F
midin-2-yl)piperidin-
4-yl)acetamide
5-(((S)-1-(((S)-2-oxo-
1-(1-(5-
(trifluoromethyl)pyri
midin-2-yl)piperidin- F 7 NH
C\)\ H = LCMS (ESI,
26A 4-yl)pyrrolidin-3- 0
m/z): 549.2
N [M+H]+
yOamino)propan-2- FF
yl)amino)-4-
(trifluoromethyl)pyri
dazin-3(2H)-one
5-(((S)-1-(((R)-2-
oxo-1-(1-(5-
(trifluoromethyl)pyri
midin-2-yl)piperidin- F 0 7 NH
H =
LCMS (ESI,
26B* 4-yl)pyrrolidin-3-
N0 m/z): 549.2
[M+H]+
yOamino)propan-2- FF
yl)amino)-4-
(trifluoromethyl)pyri
dazin-3(2H)-one
5-(((R)-1-(((S)-2-
N,NH
0
oxo-1-(1-(5-
(trifluoromethyl)pyri
LCMS (ESI,
26C
1,_NaN5.4.NNO m/z): 549.2
F N [M+H]+
midin-2-yl)piperidin-
F F
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4-yOpyrrolidin-3-
y0amino)propan-2-
yl)amino)-4-
(trifluoromethyl)pyri
dazin-3(2H)-one
5-(((R)-1-(((R)-2-
oxo-1-(1-(5-
(trifluoromethyl)pyri
midin-2-yl)piperidin- F
LCMS (ESI,
26D 4-yl)pyrrolidin-3- 0 H
F H
m/z): 549.2
F N =
[M+I-11+
yOamino)propan-2- FF
yl)amino)-4-
(trifluoromethyl)pyri
dazin-3(2H)-one
5-(((2S)-1-((1-(1-(5-
(difluoromethyl)pyri
midin-2-yl)piperidin-
N,
27 oxopyrrolidin-3- F>---051)¨NN
LCMS (ESI,
523 00
m/z): 533.2
+
yl)oxy)propan-2-
F F [M+I-11
yl)oxy)-4-
(trifluoromethyl)pyri
dazin-3(2H)-one
(S)-2-(2-((5-bromo-6-
oxo-1,6-
dihydropyridazin-4-
)<F
yl)oxy)propoxy)-N- 0
F
LCMS (ESI,
N Br
28
H 0
m/z): 549.1
methyl-N-(1-(5- 1 I +
NojLõOAõ)
(trifluoromethyl)pyri [M+H]
N
1
midin-2-yl)piperidin-
4-yl)acetamide
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5-(((2S)-1-(methyl(2-
oxo-1-(1-(5-
(trifluoromethyl)pyri
midin-2-yl)piperidin- FJ.. F
LCMS (ESI,
m/z): 563.2
29 4-yl)pyrrolidin-3- FF
yOamino)propan-2- HN,N 0
[M+H]+
yl)amino)-4-
(trifluoromethyl)pyri
dazin-3(2H)-one
6-(4-(2-oxo-3-((S)-2-
((6-oxo-5-
N,
(trifluoromethyl)-1,6- 0NH
LCMS (ESI,
30 dihydropyridazin-4-
m/z): 507.2
yl)oxy)propoxy)pyrro
F F
[M+H]+
lidin-l-yl)piperidin-
l-yl)nicotinonitrile
5-(((S)-1-(((S)-2-oxo-
1-(1-(5-
(trifluoromethyl)pyra
zin-2-yl)piperidin-4- F 0 -
N NH
LCMS (ESI,
31A* yl)pyrrolidin-3-0
na/z): 551.2
yl)oxy)propan-2- FF
[M+H]+
yl)oxy)-4-
(trifluoromethyl)pyri
dazin-3(2H)-one
5-(((S)-1-(((R)-2-
oxo-1-(1-(5-
-
(trifluoromethyl)pyra F 0
LCMS (ESI,
31B* zin-2-yl)piperidin-4- F4¨C-
nvz): 551.2
F N
yl)pyrrolidin-3- FF
[M+H]+
yl)oxy)propan-2-
yl)oxy)-4-
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(trifluoromethyl)pyri
dazin-3(2H)-one
4-bromo-5-(((S)-1- 0
)-L
(((R)-2-oxo-1-(1-(5- F 0 Br NH
- I
(trifluoromethyl)pyri
N
midin-2-yl)piperidin-
LCMS (ESI,
32
m/z): 562.2
4-yl)pyrrolidin-3-
[M+H]+
yl)oxy)propan-2-
yl)amino)pyridazin-
3(2H)-one
N-43R,4R)-3-
)<F
hydroxy-1-(5-
F
(trifluoromethyl)pyri HN-N
midin-2-yOpiperidin-
4-y1)-2-((S)-2-((6- FF
LCMS (ESI,
33A
m/z): 540.2
oxo-5-
[M+H]+
(trifluoromethyl)-1,6-
dihydropyridazin-4-
yl)amino)propoxy)ac
etamide
N-((3S,4S)-3-
hydroxy-1-(5- NDF
(trifluoromethyl)pyri HN-N 0H0 N
midin-2-yOpiperidin- ON Ws.
4-y1)-2-((S)-2-((6- FF
LCMS (ESI,
33B
m/z): 540.2
oxo-5-
[M+H]+
(trifluoromethyl)-1,6-
dihydropyridazin-4-
yl)amino)propoxy)ac
etamide
* The stereochemistry of compound was assigned by analogy to Example 10, based
on the
PARP7 potency of the more active diastereomer and in analogy to the Example
10B X-ray
crystal structure.
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The stereochemistry of compounds was arbitrarily assigned.
Intermediate 1-7: Synthesis of 3-hydroxy-I1,4'-bipiperidin]-2-one
hydrochloride
Bn-N
,--Br B c
A 0, /
0
Bn4--)--NH
j:),Boc HCI
0
0 0 JDH
____________________________________ c;1)LN
HON H HOb
Step A
To a solution of 1-benzylpiperidin-4-amine (1.91 g, 10.0 mmol, 1.0 equiv) in
water (5
mL) and ethyl acetate (10 mL) was added K2CO3(2.08 g, 15.0 mmol, 1.5 equiv)
and 5-
bromopentanoyl chloride (2.00 g, 10.0 mmol, 1.0 equiv). The reaction mixture
stirred for 1
hour and was diluted with water (20 mL) and extracted with 3 x 20 mL of ethyl
acetate. The
combined organic extracts were washed with water (10 mL), dried over anhydrous
sodium
sulfate, and concentrated in vacuo to afford 3.5 g (99% yield) of N-(1-
benzylpiperidin-4-y1)-
5-bromopentanamide as a white solid. LCMS (ESI, m/z): 355.00 [M+1-1]+.
Step B
To a solution of N-(1-benzylpiperidin-4-y1)-5-bromopentanamide (3.40 g, 9.60
mmol,
1.0 equiv) in THF (20 mL) was added t-BuOK (1.62 g, 14.4 mmol, 1.5 equiv). The
reaction
mixture stirred for 1 hour and then was quenched by the addition of water (20
mL). The
resulting solution was extracted with 3 x 50 mL of ethyl acetate, and the
combined organic
layers were dried over anhydrous sodium sulfate and concentrated in vacuo to
afford 2.5 g
(95% yield) of 1'-benzy141,4'-bipiperidin]-2-one as a white solid. LCMS (ESI,
m/z): 273.10
[M+H]+.
Step C
To a solution of 1'-benzy141,4'-bipiperidin]-2-one (2.00 g, 7.30 mmol, 1.0
equiv) in
DCM (20 mL) was added TEMPO (2.50 g, 16.0 mmol, 2.2 equiv), 3A molecular
sieves (2 g),
and Tf20 (2.28 g, 8.08 mmol, 1.1 equiv) at 0 C. The resulting solution was
stirred for 2
hours and was then diluted with water (20 mL). The solution was extracted with
3 x 50 mL of
DCM, and the combined organic layers were dried over anhydrous sodium sulfate
and
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concentrated in vacuo. The crude product was applied onto a silica gel column
eluting with
ethyl acetate/petroleum ether (4/1) to afford 1.5 g (48% yield) of 1'-benzy1-3-
((2,2,6,6-
tetramethylpiperidin-1-yl)oxy)-[1,4'-bipiperidin]-2-one as a yellow oil. LCMS
(ESI, m/z):
428.20 [M+H]+.
Step D
To a solution of l'-benzy1-3-((2,2,6,6-tetramethylpiperidin-l-y1)oxy)-[1,4'-
bipiperidin]-2-one (800 mg, 1.87 mmol, 1.0 equiv) in a mixture of AcOH, THF
and water (20
mL, 3:1:1) was added zinc powder (2.00 g, 30.6 mmol, 16 equiv). The resulting
solution was
stirred for 1 hour at 70 C. The solution was diluted with water (20 mL). The
pH of the solution
was adjusted to 12 with saturated aqueous NaOH. After filtration, the filtrate
was extracted
with 3 x 50 mL of ethyl acetate, and the organic layers were combined, dried
over anhydrous
sodium sulfate, and concentrated in vacuo. The crude product was applied onto
a silica gel
column eluting with DCM/Me0H to afford 300 mg (56% yield) of 1'-benzy1-3-
hydroxy-[1,4'-
bipiperidin]-2-one as a yellow oil. LCMS (ESI, m/z): 289.05 [M+1-1]+.
Step E
To a solution of 1'-benzy1-3-hydroxy-[1,4'-bipiperidin]-2-one (400 mg, 1.4
mmol, 1.0
equiv) in Et0H (10 mL) was added Pd/C (20 mg, 0.19 mmol, 0.1 equiv) and di-
tert-butyl
dicarbonate (605 mg, 2.77 mmol, 2.0 equiv). The resulting solution was stirred
for 1 hour
under an atmosphere of hydrogen. The solids were filtered, and the filtrate
was concentrated
.. in vacuo to afford 380 mg (92% yield) of tert-butyl 3-hydroxy-2-oxo-[1,4'-
bipiperidinel-r-
carboxylate as a colorless oil. LCMS (ESI, m/z): 299.15 [M+1-1]+.
Step F
A solution of tert-butyl 3-hydroxy-2-oxo-[1,41-bipiperidinel-1'-carboxylate
(370 mg,
1.24 mmol, 1.0 equiv) in 4M HC1 in dioxane (10 mL) was stirred for 1 hour at
room
temperature. The resulting mixture was concentrated in vacuo to afford 280 mg
(96% yield)
of 3-hydroxy-[1,4'-bipiperidin]-2-one hydrochloride as a colorless oil. LCMS
(ESI, m/z):
199.00 [M+Hl+.
Intermediate 1-8: Synthesis of 3-hydroxy-4,4-dimethy1-1-(piperidin-4-
yl)pyrrolidin-2-
one hydrochloride
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HO HO OH
0 0 )orO )0
1-J40 A )&\I
01,
ONH.HCI
Bn Boc
Step A
To a solution of 1-benzylpiperidin-4-amine (1.90 g, 9.99 mmol, 1.0 equiv), in
1-
methoxy-2-(2-methoxyethoxy)ethane (1 mL) was added Ts0H (0.28 g, 1.6 mmol, 0.2
equiv)
.. and 3-hydroxy-4,4-dimethyldihydrofuran-2(3H)-one (1.56 g, 12.0 mmol, 1.2
equiv). The
reaction mixture was irradiated with microwave radiation for 1 hour at 150 C.
The resulting
solution was stirred for an additional 2 hours at 200 C and then diluted with
ethyl acetate (2
mL). The crude product was applied onto a silica gel column eluting with
dichloromethane/methanol (9/1) to afford 840 mg (28% yield) of 1-(1-
benzylpiperidin-4-y1)-
3-hydroxy-4,4-dimethylpyrrolidin-2-one as a brown solid. LC-MS (ES, m/z):
303.00 [M+I-11+
Step B
To a solution of 1-(1-benzylpiperidin-4-y1)-3-hydroxy-4,4-dimethylpyrrolidin-2-
one
(837 mg, 2.77 mmol, 1.0 equiv) in Et0H (20 mL) was added Pd/C (80 mg, 0.75
mmol, 0.3
equiv), and di-tert-butyl dicarbonate (1.2 g, 5.5 mmol, 1.2 equiv). The
resulting solution was
stirred for 2 hours under an atmosphere of hydrogen. After filtration, the
filtrate was
concentrated in vacuo, and the crude product was applied onto a silica gel
column eluting
with ethyl acetate/petroleum ether (9/1) to afford 660 mg (76% yield) of tert-
butyl 4-(3-
hydroxy-4,4-dimethy1-2-oxopyrrolidin-1-y1)piperidine-1-carboxylate as a white
solid. LC-
MS (ES, m/z): 313.10 [M+I-11+
Step C
To a solution of tert-buty14-(3-hydroxy-4,4-dimethy1-2-oxopyrrolidin-1-
yl)piperidine-l-carboxylate (660 mg, 2.11 mmol, 1.0 equiv) in dioxane (5 mL)
was added 4M
HC1 in 1,4-dioxane (5 mL). The resulting solution stirred for 2 hours and then
was
.. concentrated in vacuo to afford 680 mg (91% yield) of 3-hydroxy-4,4-
dimethy1-1-(piperidin-
4-yl)pyrrolidin-2-one hydrochloride as a yellow solid. LCMS (ESI, m/z): 213.15
[M+H1+.
Intermediate 1-9: Synthesis of (S)-3-hydroxy-1-(piperidin-4-yl)pyrrolidin-2-
one
hydrochloride
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0 0
0
A
0 0 0
HCI
N_Boc
HO=60 0\1H
HOI,=61
Step A
To a solution of (S)-2-(2,2-dimethy1-5-oxo-1,3-dioxolan-4-yl)acetic acid (10.0
g, 57.4
mmol, 1.0 equiv) in DCM (150 mL) was added DCC (17.8 g, 86.3 mmol, 1.5 equiv),
DMAP
(701 mg, 5.74 mmol, 0.1 equiv) and ethanethiol (7.14 g, 115 mmol, 2 equiv) at
0 C. The
resulting solution was stirred for 10 min at 0 C and then for 10 hours at
room temperature.
The solids were filtered, and the filtrate was concentrated in vacuo. The
crude product was
applied on a silica gel column and was eluted with ethyl acetate/petroleum
ether (6/94) to
afford 5.8 g (47% yield) of S-ethyl (S)-2-(2,2-dimethy1-5-oxo-1,3-dioxolan-4-
ypethanethioate as a colorless oil.
Step B
To a solution of S-ethyl (S)-2-(2,2-dimethy1-5-oxo-1,3-dioxolan-4-
ypethanethioate
(5.80 g, 26.6 mmol, 1.0 equiv) in DCM (100 mL) was added triethylsilane (4.60
g, 39.5
mmol, 1.5 equiv) and Pd/C (2.00 g, 18.8 mmol, 0.7 equiv). The resulting
solution was stirred
for 3 hours at 25 C. The solids were filtered, and the filtrate was
concentrated in vacuo. The
crude product was cooled, and the isolated solid was collected to afford 5 g
of crude (S)-2-
(2,2-dimethy1-5-oxo-1,3-dioxolan-4-yl)acetaldehyde as a colorless solid.
Step C
To a solution of (S)-2-(2,2-dimethy1-5-oxo-1,3-dioxolan-4-yl)acetaldehyde
(4.90 g,
30.9 mmol, 1.0 equiv) in DCM (100 mL) was added tert-butyl 4-aminopiperidine-1-
carboxylate (9.31 g, 46.5 mmol, 1.5 equiv) and AcOH (3.72 g, 0.1 mmol, 2.0
equiv). The
resulting solution was stirred for 1 hour, and then STAB (19.7 g, 93.0 mmol,
3.0 equiv) was
added, and the reaction mixture stirred for an additional 3 hours. Saturated
aqueous NaHCO3
was added, and the aqueous layers were extracted with 2 x 50 mL of DCM. The
combined
organics were dried over anhydrous sodium sulfate and concentrated in vacuo.
The residue
was applied onto a silica gel column eluting with ethyl acetate/petroleum
ether (30/70) to
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afford 6 g (68% yield) of tert-butyl (S)-4-(3-hydroxy-2-oxopyrrolidin-1-
yl)piperidine-1-
carboxylate as a yellow solid. LCMS (ESI, m/z): 285.20 [M+Hr.
Step D
A solution of tert-butyl (S)-4-(3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-
carboxylate (6.00 g, 0.02 mmol, 1.0 equiv) in 4M HC1 in dioxane (15 mL) was
stirred for 1
hour and then was concentrated to afford 4.5 g (96% yield) of (S)-3-hydroxy-1-
(piperidin-4-
yl)pyrrolidin-2-one hydrochloride as a yellow solid. LCMS (ESI, m/z): 185.10
[M+Hr.
Intermediate I-11: Synthesis of (R)-1-((1R,5S,6s)-3-azabicyclo[3.1.01hexan-6-
y1)-3-
hydroxypyrrolidin-2-one hydrogen chloride
0 0 H
HCI
HO¶
H2NN--N¨Boc ___________ A N¨Boc ____________ N NH
Step A
To a solution of tert-butyl (1R,5S,6s)-6-amino-3-azabicyclo[3.1.01hexane-3-
carboxylate (2.00 g, 10.1 mmol, 1.0 equiv) in DCM (40 mL) was added 2-[(4R)-
2,2-
dimethy1-5-oxo-1,3-dioxolan-4-yllacetaldehyde (5.00 g, 31.6 mmol, 3.1 equiv)
and AcOH
(0.20 g, 3.33 mmol, 0.3 equiv). The reaction mixture stirred for 1 hour, and
then STAB (4.10
g, 19.4 mmol, 1.9 equiv) was added, and the reaction was stirred for an
additional 1.5 hours.
The solution was washed with 2 x 50 mL of aqueous NaHCO3, and the organic
layers were
combined, dried over anhydrous sodium sulfate and concentrated. The crude
product was
applied onto a silica gel column eluting with ethyl acetate/Me0H (4/1) to
afforded 600 mg
(21% yield) of tert-butyl (1R,5S,6s)-6-((R)-3-hydroxy-2-oxopyrrolidin-1-y1)-3-
azabicyclo[3.1.01hexane-3-carboxylate as a yellow solid. LCMS (ESI, m/z):
283.15 [M+Hr.
Step B
A solution of tert-butyl (1R,5S,6s)-6-((R)-3-hydroxy-2-oxopyrrolidin-1-y1)-3-
azabicyclo[3.1.01hexane-3-carboxylate (600 mg, 2.13 mmol, 1.0 equiv) in 4M HC1
in
dioxane (5 mL) was stirred for 1 hour. The mixture was concentrated to afford
400 mg
(crude) of (R)-1-((lR,5S,6s)-3-azabicyclo[3.1.01hexan-6-y1)-3-
hydroxypyrrolidin-2-one
hydrogen chloride as a yellow solid. LCMS (ES, m/z): 183.20 [M+1-11+.
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Intermediate 1-12: Synthesis of (3R,4S)-3-hydroxy-4-methyl-1-(piperidin-4-
yl)pyrrolidin-2-one hydrochloride and (35,4R)-3-hydroxy-4-methyl-1-(piperidin-
4-
yl)pyrrolidin-2-one hydrochloride
oBn
0 0 -Bn
A
_________________________ -
0
0 o,Bn
____________________________ H0.6
N
o
N,Boc
HO(/('')
0 NH HCI 0 NH HCI
___________________________________ HO }y)
o
N,Boc
HO,,p
Step A
To a solution of 4-methyldihydrofuran-2(3H)-one (5.30 g, 52.9 mmol, 1.0 equiv)
in
diethylene glycol dimethyl ether (4 mL) was added 1-benzylpiperidin-4-amine
(15.1 g, 79.4
mmol, 1.5 equiv) and 4-methylbenzenesulfonic acid (1.37 g, 7.94 mmol, 0.2
equiv). The
resulting solution was stirred for 16 hours at 180 C and then was diluted
with 6 mL of ethyl
acetate and applied onto a silica gel column eluting with
dichloromethane/methanol (87/13)
to afford 2.49 g (17% yield) of 1-(1-benzylpiperidin-4-y1)-4-methylpyrrolidin-
2-one as a
yellow oil. LCMS (ESI, m/z): 273.05 [M+Hr.
Step B
To a solution of 1-(1-benzylpiperidin-4-y1)-4-methylpyrrolidin-2-one (3.10 g,
11.4
mmol, 1.0 equiv) in DCM (20 mL) under a nitrogen atmosphere was added 3A
molecular
sieves (2 g), TEMPO (3.91 g, 25.0 mmol, 2.2 equiv) and Tf20 (6.42 g, 22.8
mmol, 2.0 equiv)
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at 0 C. The resulting solution was stirred for 30 min and then for another 2
hours at room
temperature. The solids were filtered, and the filtrate was then concentrated
and applied onto
a silica gel column eluting with dichloromethane/methanol (97/3) to afford 1.3
g (20% yield)
of (3R,4S)-1-(1-benzylpiperidin-4-y1)-4-methy1-3-((2,2,6,6-
tetramethylpiperidin-1-
yl)oxy)pyrrolidin-2-one and (3S,4R)-1-(1-benzylpiperidin-4-y1)-4-methy1-3-
((2,2,6,6-
tetramethylpiperidin-1-yl)oxy)pyrrolidin-2-one as a yellow solid. LCMS (ESI,
m/z): 428.30
[M+H]+.
Step C
To a mixture of (3R,4S)-1-(1-benzylpiperidin-4-y1)-4-methy1-3-((2,2,6,6-
tetramethylpiperidin-l-yl)oxy)pyrrolidin-2-one and (3S,4R)-1-(1-
benzylpiperidin-4-y1)-4-
methy1-3-((2,2,6,6-tetramethylpiperidin-1-yl)oxy)pyrrolidin-2-one (1.30 g,
3.04 mmol, 1.0
equiv) in AcOH/THF/water (15 mL, 3:1:1) was added Zn (3.98 g, 60.8 mmol, 20
equiv). The
resulting solution was stirred for 2 hours at 70 C and then was diluted with
water (15 mL).
The pH was adjusted to 12 with aqueous NaOH and extracted with 3 x 30 mL of
ethyl
acetate. The combined organic layers were dried over anhydrous sodium sulfate
and
concentrated in vacuo. The crude product was applied onto a silica gel column
eluting with
dichloromethane/methanol (93/7) to afford 180 mg (21% yield) of (3R,4S)-1-(1-
benzylpiperidin-4-y1)-3-hydroxy-4-methylpyrrolidin-2-one and (3S,4R)-1-(1-
benzylpiperidin-4-y1)-3-hydroxy-4-methylpyrrolidin-2-one as yellow oil. LCMS
(ESI, m/z):
289.20 [M+1-11+.
Step D
To a solution of (3R,4S)-1-(1-benzylpiperidin-4-y1)-3-hydroxy-4-
methylpyrrolidin-2-
one and (3S,4R)-1-(1-benzylpiperidin-4-y1)-3-hydroxy-4-methylpyrrolidin-2-one
in Me0H (4
mL) was added di-tert-butyl dicarbonate (272 mg, 1.25 mmol, 2.0 equiv) and
Pd/C (7 mg,
0.06 mmol, 0.1 equiv). The resulting solution was stirred for 1 hour under an
atmosphere of
hydrogen. The solids were filtered, and the filtrate was concentrated to
afford 226 mg of
crude tert-butyl (3R,4S)-4-(3-hydroxy-4-methy1-2-oxopyrrolidin-1-y1)piperidine-
1-
carboxylate and tert-buty1(3S,4R)-4-(3-hydroxy-4-methy1-2-oxopyrrolidin-1-
y1)piperidine-1-
carboxylate as a yellow oil. LCMS (ESI, m/z): 299.05 [M+Hr.
Step E
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A solution of crude tert-butyl (3R,4S)-4-(3-hydroxy-4-methy1-2-oxopyrrolidin-1-
yl)piperidine-1-carboxylate and tert-butyl (3S,4R)-4-(3-hydroxy-4-methy1-2-
oxopyrrolidin-1-
yl)piperidine-1-carboxylate (226 mg, 0.76 mmol, 1.0 equiv) in HC1/dioxane (10
mL, 4 M)
was stirred for 1 hour and then was concentrated to afford 168 mg of crude
(3R,4S)-3-
hydroxy-4-methy1-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride and (3S,4R)-
3-hydroxy-
4-methy1-1-(piperidin-4-yOpyrrolidin-2-one hydrochloride as a white solid.
LCMS (ESI,
m/z): 199.05 [M+H]+.
Intermediate 1-13: Synthesis of (R)-1-((3R,4R)-3-fluoropiperidin-4-y1)-3-
hydroxypyrrolidin-2-one-TFA salt and (R)-1-((35,45)-3-fluoropiperidin-4-y1)-3-
hydroxypyrrolidin-2-one-TFA salt
Boc ,Boc
,Boc
,Boc F.01
0
+ 0
,b1
H2N A HOw
H2N HO""biss.
CF3CO2H
CF3CO2H
Fit,, NH
0
,Z131 0
HO
HO
Step A
To a solution of tert-butyl (3R,4R)-4-amino-3-fluoropiperidine-1-carboxylate
and tert-
butyl (3S,4S)-4-amino-3-fluoropiperidine-1-carboxylate (1.00 g, 4.51 mmol, 1.0
equiv) in
DCM (20 mL) was added (R)-2-(2,2-dimethy1-5-oxo-1,3-dioxolan-4-yl)acetaldehyde
(1.10 g,
6.96 mmol, 1.5 equiv) and AcOH (1.70 g, 0.03 mmol, 0.01 equiv). The resulting
solution was
stirred for 1 hour, and then STAB (2.90 g, 0.01 mmol, 3.0 equiv) was added,
and the reaction
mixture stirred for an additional 3 hours. The reaction was quenched by the
addition of
saturated aqueous NaHCO3. The aqueous layer was extracted with 2 x 50 mL of
DCM. The
combined organic layers were dried over anhydrous sodium sulfate and
concentrated in
vacuo. The residue was applied onto a silica gel column eluting with Me0H/DCM
(5/95) to
afford 700 mg (51% yield) of tert-butyl (3R,4R)-3-fluoro-4-((R)-3-hydroxy-2-
oxopyrrolidin-
1-yl)piperidine-1-carboxylate and tert-butyl (3S,45)-3-fluoro-4-((R)-3-hydroxy-
2-
oxopyrrolidin-1-yl)piperidine-1-carboxylate as an off-white oil.
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Step B
To a solution of tert-butyl (3R,4R)-3-fluoro-4-((R)-3-hydroxy-2-oxopyrrolidin-
1-
yl)piperidine-1-carboxylate and tert-butyl (3S,4S)-3-fluoro-4-((R)-3-hydroxy-2-
oxopyrrolidin-1-yl)piperidine-1-carboxylate (700 mg, 2.32 mmol, 1.0 equiv) in
DCM (5 mL)
was added TFA (0.5 mL). The resulting solution was stirred for 1 hour and then
concentrated
to afford 600 mg of crude (R)-1-((3R,4R)-3-fluoropiperidin-4-y1)-3-
hydroxypyrrolidin-2-one-
TFA salt and (R)-1-((3S,4S)-3-fluoropiperidin-4-y1)-3-hydroxypyrrolidin-2-one-
TFA salt as a
brown oil.
Intermediate 1-14: Synthesis of (R)-1-((3R,4S)-3-fluoropiperidin-4-y1)-3-
hydroxypyrrolidin-2-one hydrochloride and (R)-1-((35,4R)-3-fluoropiperidin-4-
y1)-3-
hydroxypyrrolidin-2-one hydrochloride
F F-, FBoc F,õ. ,Boc
\ \ H2N N-Boc + H2N1,.( N-Boc A ...--
___________ / / 0
+
HO.--61 0 N
F,,
B 0 F\IH HCI 0 '- NH HCI
______________ - HO.--tN +
HO.-a'µ.)
Step A
To a solution of (R)-2-(2,2-dimethy1-5-oxo-1,3-dioxolan-4-yOacetaldehyde (2.90
g,
18.34 mmol, 4.0 equiv) in DCM (20 mL) was added AcOH (550 mg, 9.16 mmol, 2.0
equiv)
and a mixture of tert-butyl (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylate
and tert-butyl
(3R,4S)-4-amino-3-fluoropiperidine-1-carboxylate (1.00 g, 4.51 mmol, 1.0
equiv). The
resulting solution was stirred for 0.5 hours, and then STAB (2.91 g, 13.74
mmol, 3.0 equiv)
was added, and the reaction was stirred for an additional 3 hours. The
reaction was then
quenched by the addition of 20 mL of aqueous NaHCO3. The resulting solution
was extracted
with 3 x 50 mL of DCM. The organic layers were combined, dried over anhydrous
sodium
sulfate and concentrated in vacuo. The crude product was applied onto a silica
gel column
eluting with dichloromethane/methanol (2/3) to afford 0.66 g (48% yield) of
tert-butyl
(3S,4R)-3-fluoro-4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-
carboxylate and tert-
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butyl (3R,4S)-3-fluoro-4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-
carboxylate as
yellow oil. LCMS (ESI, m/z): 303.15 [M+Hr.
Step B
A solution of tert-butyl (3S,4R)-3-fluoro-4-((R)-3-hydroxy-2-oxopyrrolidin-1-
yl)piperidine-l-carboxylate and tert-butyl (3R,4S)-3-fluoro-4-((R)-3-hydroxy-2-
oxopyrrolidin-l-yl)piperidine-1-carboxylate (660 mg, 2.18 mmol, 1.0 equiv) in
HC1/dioxane
(15 mL, 4 M) was stirred for 15 hours. The resulting mixture was concentrated
to afford 510
mg (98% yield) of (R)-1-((3R,4S)-3-fluoropiperidin-4-y1)-3-hydroxypyrrolidin-2-
one
hydrochloride and (R)-1-((3S,4R)-3-fluoropiperidin-4-y1)-3-hydroxypyrrolidin-2-
one
hydrochloride as a yellow oil. LCMS (ESI, m/z): 203.15 [M+I-11+.
Intermediate I-15: Synthesis of (R)-1-((R)-3,3-difluoropiperidin-4-y1)-3-
hydroxypyrrolidin-2-one hydrochloride and (R)-1-((S)-3,3-difluoropiperidin-4-
y1)-3-
hydroxypyrrolidin-2-one hydrochloride
OH OH
)LNH2 0 0
F A FB F
Bi oc N NH HCI
Boc
.. Step A
To a solution of tert-butyl 4-amino-3,3-difluoropiperidine-1-carboxylate (1.00
g, 4.23
mmol, 1.0 equiv) in DCM (50 mL) was added (R)-2-(2,2-dimethy1-5-oxo-1,3-
dioxolan-4-
yOacetaldehyde (1004 mg, 6.35 mmol, 1.5 equiv), STAB (3.59 g, 16.9 mmol, 4.0
equiv) and
AcOH (250 mg, 4.2 mmol, 1.0 equiv). The resulting solution stirred for 12
hours and was
concentrated in vacuo. The crude product was applied onto a silica gel column
with eluting
DCM/methanol (9/1) to afford 1.5 g (crude) of tert-butyl 3,3-difluoro-4-((R)-3-
hydroxy-2-
oxopyrrolidin-l-yl)piperidine-1-carboxylate as a yellow solid. LCMS (ESI,
m/z): 321.30
[M+H]+.
Step B
A solution of tert-butyl 3,3-difluoro-4-((R)-3-hydroxy-2-oxopyrrolidin-1-
yl)piperidine-1-carboxylate (1.50 g, 4.68 mmol, 1.0 equiv) in 4M HC1 in
dioxane (10 mL)
was stirred for 6 hours and was then concentrated in vacuo to afford 1.5 g
(crude) of (R)-1-
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((R)-3,3-difluoropiperidin-4-y1)-3-hydroxypyrrolidin-2-one hydrochloride and
(R)-1-((S)-3,3-
difluoropiperidin-4-y1)-3-hydroxypyrrolidin-2-one hydrochloride as a yellow
oil. LCMS
(ESI, m/z): 221.10 [M+Hr.
Intermediate 1-16: Synthesis of (1-(4-methoxybenzy1)-6-oxo-5-(trifluoromethyl)-
1,6-
dihydropyridazin-4-y1)-L-alanine
0
0 F3CN,PMB
F3C).-LN PMB I '
' HNN
0
To a solution of 5-chloro-2-(4-methoxybenzy1)-4-(trifluoromethyppyridazin-
3(2H)-
one (2.00 g, 6.28 mmol, 1.0 equiv) in DMF (15 mL) was added L-alanine (725 mg,
8.14
mmol, 1.3 equiv) and K2CO3 (2.60 g, 18.8 mmol, 3.0 equiv). The resulting
solution was
.. stirred for 2 hours at 60 C and then was quenched by the addition of 100
mL of water. The
pH was adjusted to 2-3 with aqueous 1N HC1. The solution was extracted with 3
x 150 mL of
DCM. The organic layers were combined, dried over anhydrous sodium sulfate and
concentrated in vacuo. The crude product was applied onto a reverse phase
column eluting
with water/CH3CN (1/1) to afford 1.4 g (60% yield) of (1-(4-methoxybenzy1)-6-
oxo-5-
.. (trifluoromethyl)-1,6-dihydropyridazin-4-y1)-L-alanine as a light yellow
solid. LCMS (ES,
m/z): 372.11 [M+H]+.
Examples 34-37
Examples 34-37 were synthesized according to the procedures described for the
synthesis of 5-((S)-14(S)-1-(1-(5-(trifluoromethyppyrimidin-2-yOpiperidin-4-
y1)-2-
oxopyrrolidin-3-yloxy)propan-2-ylamino)-4-(trifluoromethyppyridazin-3(21-1)-
one and 5-
((5)-1-((R)-1-(1-(5-(trifluoromethy Opy rimi din-2-y Opip eri din-4-y 0-2-
oxopyrroli din-3-
yloxy)propan-2-ylamino)-4-(trifluoromethyl)pyridazin-3(21-1)-one (see Example
10) using
appropriate building blocks and modified reaction conditions (such as reagent
ratio,
temperature, coupling conditions, and reaction time) as needed. The relative
stereochemistry
of compounds was assigned by analogy to Example 10, based on the PARP7 potency
of the
more active diastereomer and in analogy to the Example 10B X-ray crystal
structure.
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Example
Structure Analytical Data
No.
LCMS (ESI, m/z): 564.20
[M+Hr; 11-1 NMR (300
MHz, DMSO-d6) 6: 12.42 (s,
0
F3C L NH N 1H), 8.69 (d, J = 0.9 Hz,
HNN 0
2H), 7.92 (s, 1H), 6.48 (br,
õõ=0õ 1H), 4.83 (d, J = 12.9 Hz,
34A
1H), 4.57 ¨ 4.45 (m, 1H),
(S)-3-((S)-2-46-oxo-5-(trifluoromethyl)-1,6- 4.20 ¨ 4.00 (m, 1H), 3.86 ¨
dihydropyridazin-4-yl)amino)propoxy)-1'-(5-
3.78 (m, 2H), 3.62 ¨ 3.53 (m,
(trifluoromethyl)pyrimidin-2-y1)-[1,4'-
bipiperidin]-2-one 1H), 3.20 ¨ 2.90 (m, 4H),
1.95¨ 1.51 (m, 8H), 1.16 (d,
J = 6.3 Hz, 3H).
LCMS (ESI, m/z): 564.20
[M+H]+;11-1NMR (300
0 MHz, DMSO-d6) 6: 12.45 (s,
F3C)NH N
( CF3 1H), 8.69 (d, J = 0.9 Hz,
I
HNN 0
2H), 7.94 (s, 1H), 6.47 (br,
N N
1H), 4.84 (d, J = 12.9 Hz,
0"
34B
1H), 4.65 ¨ 4.35 (m, 1H),
(R)-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6- 4.22 ¨ 4.01 (m, 1H), 3.89 ¨
dihydropyridazin-4-yl)amino)propoxy)-1'-(5-
(trifluoromethyl)pyrimidin-2-y1)-[1,4'- 3.72 (m, 2H), 3.68 ¨ 3.58 (m,
bipiperidin]-2-one 1H), 3.15 ¨2.90 (m, 4H),
2.00¨ 1.47 (m, 8H), 1.15 (d,
J = 6.3 Hz, 3H).
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Example
Structure Analytical Data
No.
LCMS (ESI, m/z): 578.30
[M+H1+;11-INMR (400
MHz, DMSO-d6) 6 12.38 (s,
0
F3C 1H), 8.69 (s, 2H), 7.93 (s,
HN 1H), 6.39 (br, 1H), 4.80 (d, J
= 13.2 Hz, 2H), 4.27 ¨ 4.21
35A
(m, 1H), 4.09 ¨ 03(n4. 2H),
5-(((S)-1-(((S)-4,4-dimethy1-2-oxo-1-(1-(5- 1H), 3.09 ¨ 3.00 (m, 2H),
(trifluoromethyppyrimidin-2-yOpiperidin-4-
yOpyrrolidin-3-y0oxy)propan-2-y0amino)-4- 2.91 (s, 2H), 1.67 ¨ 1.46 (m,
(trifluoromethyl)pyridazin-3(2H)-one 4H), 1.17 (d, J = 6.5 Hz,
3H), 1.00 (s, 3H), 0.77 (s,
3H).
LCMS (ESI, m/z): 578.30
[M+H1+;11-INMR (400
0 MHz, DMSO-d6) 6 12.45 (s,
F3C)L 1\1H 1H), 8.69 (s, 2H), 7.95 (s,
HNN
1H), 6.30 (br, 1H), 4.80 (d, J
= 13.2 Hz, 2H), 4.26 ¨ 4.18
35B
-CN N (m, 1H), 4.10 ¨ 4.04 (m, 1H),
CF3
4.00 ¨ 3.96 (m, 1H), 3.68 ¨
5-(((S)-1-(((R)-4,4-dimethy1-2-oxo-1-(1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4- 3.63 (m, 2H), 3.07 ¨ 3.00 (m,
yOpyrrolidin-3-y0oxy)propan-2-y0amino)-4- 2H), 2.92 (s, 2H), 1.66¨ 1.48
(trifluoromethyl)pyridazin-3(2H)-one
(m, 4H), 1.19 (d, J= 6.4 Hz,
3H), 1.04 (s, 3H), 0.85 (s,
3H).
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Example
No. Structure Analytical Data
0
F3C
HN A\I
36A LCMS (ESI, m/z): 492.25
[M+H]+
(R)-6-(4-(2-oxo-3-(2-((6-oxo-5-
(trifluoromethyl)-1,6-dihydropyridazin-4-
yl)amino)ethoxy)pyrrolidin-1-yl)piperidin-1-
yl)nicotinonitrile
0
F3C
HNN
36B c-0,
,d LCMS (ESI, m/z): 492.25
N----CN [M+H]+
(S)-6-(4-(2-oxo-3-(2-((6-oxo-5-
(trifluoromethyl)-1,6-dihydropyridazin-4-
yl)amino)ethoxy)pyrrolidin-1-yl)piperidin-1-
yl)nicotinonitrile
0
F3C NH
I
37A HNN
CF3 LCMS (ESI, m/z): 564.20
5-(((S)-1-(((3S,4R)-4-methy1-2-oxo-1-(1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-
yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-
(trifluoromethyl)pyridazin-3(2H)-one
0
F3CNH
HNN 0
37B
N-CCF3 LCMS (ESI, m/z): 564.20 [M+I-11+
5-4(S)-1-(43R,45)-4-methy1-2-oxo-1-(1-(5-
(trifluoromethyppyrimidin-2-yOpiperidin-4-
yOpyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-
(trifluoromethyl)pyridazin-3(2H)-one
Examples 38-40
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Examples 38-40 were synthesized according to the procedures described for the
synthesis of 5-((S)-1-((S)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yOpiperidin-4-
y1)-2-
oxopyrrolidin-3-yloxy)propan-2-ylamino)-4-(trifluoromethyppyridazin-3(211)-one
and 5-
((S)-1-((R)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-y1)-2-
oxopyrrolidin-3-
yloxy)propan-2-ylamino)-4-(trifluoromethyl)pyridazin-3(2H)-one (see Example
10) using
appropriate building blocks and modified reaction conditions (such as reagent
ratio,
temperature, coupling conditions, and reaction time) as needed. The absolute
stereochemistry
of the substituted piperidine moieties was arbitrarily assigned.
Example
No. Structure Analytical Data
0
F3CaNH
HN 0 N¨ rs,
38A LCMS (ESI, m/z): 568.20
5 -(((S)-1-(((R)-1-((3R,4R)-3 -fluoro-1 -(5 -
(trifluoromethyppyrimidin-2-yOpiperidin-4-y1)-
2-oxopyrrolidin-3-y0oxy)propan-2-y0amino)-
4-(trifluoromethyl)pyridazin-3(2H)-one
0
F3C"'NH
HN 0 b
38B
N.--µ CF3 LCMS (ESI, m/z): 568.20
Li N [M+1-11+;
5-(((S)-1-(((R)-1-((3S,45)-3-fluoro-1-(5-
(trifluoromethyppyrimidin-2-yOpiperidin-4-y1)-
2-oxopyrrolidin-3-y0oxy)propan-2-y0amino)-
4-(trifluoromethyl)pyridazin-3(2H)-one
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Example
Structure Analytical Data
No.
0 LCMS (ESI, m/z): 568.15
, NH [M+H]+;
1\1
HN 0 Fv_\ 1H NMR (400 MHz, DMS0-
JL
cF3
5-(((S)-1-(((R)-1-((3S,4R)-3-fluoro-1-(5- 2H), 7.95 (s, 1H), 6.33 - 6.31
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-y1)- (m, 1H), 5.08 (t, J= 11.6 Hz,
2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-
4-(trifluoromethyl)pyridazin-3(2H)-one 1H), 4.97 - 4.86 (m, 2H),
4.29 -4.13 (m, 3H), 3.83 (dd,
39A
J = 10.0, 6.3 Hz, 1H), 3.62
(dd, J = 10.0, 4.8 Hz, 1H),
3.43 - 3.33 (m, 2H), 3.30 ¨
3.24 (m, 1H), 3.19 (t, J=
12.6 Hz, 1H), 2.33 - 2.23 (m,
1H), 2.02¨ 1.89 (m, 1H),
1.84¨ 1.74(m, 1H), 1.68 -
1.62 (m, 1H), 1.18 (d, J= 6.4
Hz, 3H).
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Example
Structure Analytical Data
No.
LCMS (ESI, m/z): 568.10
[M+H]+;
1FINMR (400 MHz, DMSO-
d6) 6 12.46 (s, 1H), 8.71 (s,
2H), 7.95 (s, 1H), 6.32 - 6.30
0 (m, 1H),5.09 (t, J= 11.6 Hz,
F3CNH 1H), 4.98 ¨ 4.83 (m, 2H),
I
HN 0 F-õ 4.37 ¨ 4.14 (m, 3H), 3.83
39B
CF3
(dd, J = 10.0, 6.5 Hz, 1H),
5-(((S)-1-(((R)-1-((3R,45)-3-fluoro-1-(5- 3.62 (dd, J= 10.0, 4.7 Hz,
(trifluoromethyppyrimidin-2-yOpiperidin-4-y1)- 1H), 3.45 ¨ 3.35 (m, 1H),
2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-
3.33 - 3.30 (m, 1H), 3.28 ¨4-(trifluoromethyl)pyridazin-3(2H)-one
3.12 (m, 2H), 2.33 - 2.23 (m,
1H), 2.02¨ 1.89 (m, 1H),
1.84¨ 1.74(m, 1H), 1.68 -
1.62 (m, 1H), 1.18 (d, J= 6.4
Hz, 3H).
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Example
Structure Analytical Data
No.
0 LCMS (ESI, m/z): 542.15
F3Cj-(
NH [M+I-11+;
I I
HN N 1-1-1NMR (300 MHz, DMS0-
F F d6) 6 12.45 (s, 1H), 8.50 (d,
J = 2.1 Hz, 1H), 7.94(s,
/ CN 1H),7.92 ¨ 7.89 (m, 1H),
6-((R)-3,3-difluoro-4-((R)-2-oxo-3-((S)-2-46- 7.11 (d, J= 9.2 Hz, 1H),
oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-
40A 6.31- 6.26 (m" 1H) 4.90-4.88
4-yl)amino)propoxy)pyrrolidin-1-y1)piperidin-
1-yl)nicotinonitrile (m, 1H), 4.70-4.50 (m, 2H),
4.25-4.12 (m, 2H), 3.90-3.80
(m, 1H), 3.70 ¨ 3.65 (m, 1H),
3.55 -3.45(m, 1H), 3.43-3.38
(m, 2H), 3.29-3.22 (m, 1H),
2.28-2.20 (m, 1H), 1.85-1.72
(m, 3H), 1.16 (d, J= 6.5 Hz,
3H).
LCMS (ESI, m/z): 542.15
[M+H]+;
1FINMR (300 MHz, DMSO-
d6) 6 12.44 (s, 1H), 8.50 (d, J
0 = 2.3 Hz, 1H), 7.96(s,
F3Cj=L
NH 1H)7.94-7.85 (m, 1H), 7.11
HN (d, J = 9.1 Hz, 1H), 6.31 -
40B "k-0 F F 6.25(m, 1H), 4.87-4.80(m,
1\11.= 1H), 4.72-4.65 (m, 2H),
N CN
4.35 -4.22(m, 2H), 3.85-3.80
6-((S)-3,3-difluoro-4-((R)-2-oxo-3-((S)-2-((6-
oxo-5-(trifluoromethyl)-1,6-dihydropyridazin- (m, 1H), 3.70-3.63 (m, 1H),
4-yl)amino)propoxy)pyrrolidin-1-y1)piperidin- 3.55-3.35 (m, 2H), 3.31-3.17
1-yl)nicotinonitrile
(m, 2H), 2.32-2.28 (m, 1H),
2.02-1.90 (m, 1H), 1.73-1.67
(m, 2H), 1.16 (d, J= 6.4 Hz,
3H).
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Examples 41-45
Examples 41-45 were synthesized according to the procedures described for the
synthesis of 5-4(S)-1-4(R)-1-(1-(5-chloropyrimidin-2-yOpiperidin-4-y1)-2-
oxopyrrolidin-3-
yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (see Example
16) using
appropriate building blocks and modified reaction conditions (such as reagent
ratio,
temperature, coupling conditions, and reaction time) as needed.
Example
Structure Analytical Data
No.
0
F3C
NH
I NI
HN 0
41 LCMS (ESI, m/z): 516.10
M+H+
5-(((S)-1-(((R)-1-(1-(5-chloropyrazin-2-
[ I
yl)piperidin-4-y1)-2-oxopyrrolidin-3-
yl)oxy)propan-2-yl)amino)-4-
(trifluoromethyl)pyridazin-3(2H)-one
0
NH
HN N
1040
42 C/1 LCMS (ESI, m/z): 500.20
5-(((S)-1-(((R)-1-(1-(5-fluoropyrimidin-2-
yl)piperidin-4-y1)-2-oxopyrrolidin-3-
yl)oxy)propan-2-yl)amino)-4-
(trifluoromethyl)pyridazin-3(2H)-one
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Example
Structure Analytical Data
No.
F3C
NH
NI
HN
43 / CF3 LCMS (ESI, m/z): 548.20
[M+H]+
5-(((S)-1-(((R)-2-oxo-1-((1R,5S,6s)-3-(5-
(trifluoromethyl)pyrimidin-2-y1)-3-
azabicyclo[3.1.0lhexan-6-y1)pyrrolidin-3-
y1)oxy)propan-2-y1)amino)-4-
(trifluoromethyl)pyridazin-3(2H)-one
0 LCMS (ESI, m/z): 496.52
F3Cj.
NH [M+41;
HNN NMR (400 MHz, CDC13)
6 ppm 1.25 (s, 2 H) 1.33 (br
d, J= 6.36 Hz, 4 H) 1.44 (br
s, 1 H) 1.50 - 1.60 (m, 5 H)
5-(((S)-1-(((R)-1-(1-(5-methylpyrimidin-2-
1.63 - 1.75 (m, 3 H) 1.92 (br
yl)piperidin-4-y1)-2-oxopyrrolidin-3-
dd, J= 14.18, 7.34 Hz, 1 H)
yl)oxy)propan-2-yl)amino)-4-
2.03 (s, 1 H) 2.12 (s, 3 H)
44 (trifluoromethyl)pyridazin-3(2H)-one
2.28 - 2.38 (m, 1 H) 2.87 -
2.97 (m, 2 H) 3.15 - 3.23 (m,
1 H) 3.28 - 3.36 (m, 1H)
3.71 (br dd, J= 9.78, 4.40
Hz, 1 H) 3.91 - 4.00 (m, 1 H)
4.05 (t, J= 7.58 Hz, 1 H)
4.13 -4.26 (m, 2 H) 4.84 (br
dd, J= 9.54, 2.69 Hz, 2 H)
5.96 (br s, 1 H) 7.70 (s, 1 H)
8.15 (s, 2 H).
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Example
No. Structure Analytical Data
LCMS (ESI, m/z): 507.43
[M+H]+;
'H NMR (CDC13, 400 MHz)
6 10.46 (br s, 1H), 8.32 (s,
1H), 8.15 (s, 1H), 7.71 (s,
0 1H), 5.8-6.0 (m, 1H), 4.60
F3C NH (br t, 2H, J= 14.7 Hz),
4.26
HNN (if, 1H, J= 4.3, 12.1 Hz),
0 4.1-4.2 (m, 1H), 4.05 (dd,
45 1H, J= 6.6, 7.6 Hz), 3.9-
4.0
5-(4-((R)-2-oxo-3-((S)-2-((6-oxo-5- 3.9, 9.8 Hz), 3.30 (dt, 1H,
J=
(trifluoromethyl)-1,6-dihydropyridazin-4- 4.4, 9.0 Hz), 3.2-3.2 (m,
1H),
yl)amino)propoxy)pyrrolidin-1-yl)piperidin-1- 3.0-3.1 (m, 2H), 2.3-2.4
(m,
yl)pyrazine-2-carbonitrile 1H), 1.9-2.0 (m, 1H), 1.83
(br d, 2H, J= 11.7 Hz), 1.6-
1.7 (m, 2H), 1.5-1.6 (m, 1H),
1.32 (d, 3H, J=6.8 Hz), 1.25
(s, 2H).
Examples 46-49
Examples 46-49 were synthesized according to the procedures described for the
synthesis of 5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-
yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one
and 5-(((S)-
1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-
yl)pyrrolidin-3-
yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one (see Examples
20A and
20B) using appropriate building blocks and modified reaction conditions (such
as reagent
ratio, temperature, coupling conditions, and reaction time) as needed. The
relative
stereochemistry of compounds was assigned by analogy to Example 10, based on
the PARP7
potency of the more active diastereomer and in analogy to the Example 10B X-
ray crystal
structure.
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Example
Structure Analytical Data
No.
0 LCMS (ESI, m/z): 563.10
BrNH
[M+H]+;
1H NMR (300 MHz,
DMSO-d6) 6 12.42 (s, 1H),
r"--N 8.69 (d, J = 0.9 Hz, 2H), 7.92
j--CF3
(s, 1H), 6.48 (br s, 1H), 4.83
46A
4-bromo-5-(((S)-1-(((S)-2-oxo-1-(1-(5- (d, J = 12.9 Hz, 1H), 4.57 -
(trifluoromethyl)pyrazin-2-yl)piperidin-4-
4.45 (m, 1H), 4.20 - 4.00 (m,
yOpyrrolidin-3-y0oxy)propan-2-
yl)oxy)pyridazin-3(2H)-one 1H), 3.86 - 3.78 (m, 2H),
3.62 - 3.53 (m, 1H), 3.20 -
2.90 (m, 4H), 1.95- 1.51
(m, 8H), 1.16 (d, J= 6.3 Hz,
3H).
LCMS (ESI, m/z): 563.10
[M+H]+;
0 1H NMR (300 MHz,
Br)-LNH
DMSO-d6) 6 12.45 (s, 1H),
8.69 (d, J = 0.9 Hz, 2H), 7.94
"".--0
46B (s, 1H), 6.47 (br s, 1H), 4.84
(d, J = 12.9 Hz, 1H), 4.65 -
\\
4.35 (m, 1H), 4.22 - 4.01 (m,
4-bromo-5-(((S)-1-(((R)-2-oxo-1-(1-(5- 1H), 3.89 - 3.72 (m, 2H),
(trifluoromethyppyrazin-2-yOpiperidin-4-
yOpyrrolidin-3-y0oxy)propan-2- 3.68 - 3.58 (m, 1H), 3.15 -
yl)oxy)pyridazin-3(2H)-one 2.90 (m, 4H), 2.00 - 1.47
(m, 8H), 1.15 (d, J= 6.3 Hz,
3H).
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Example
No. Structure Analytical Data
LCMS (ESI, m/z): 517.10
[M+H]+;
CI)L0 NH 11-1 NMR(300 MHz, DMS0-
I I d6) 6 13.22 (s, 1H), 8.70 (s,
oN
2H), 8.21 (s, 1H), 5.30¨ 5.10
47A (m, 1H), 4.83 (d, J= 13.5
NNN
Hz, 2H), 4.21 ¨ 3.90 (m,
3H), 3.72 ¨ 3.61 (m, 1H),
4-chloro-5-4(S)-1-4(S)-2-oxo-1-(1-(5-
(trifluoromethyppyrimidin-2-yOpiperidin-4- 3.25 ¨ 2.98 (m, 4H), 2.27 ¨
yOpyrrolidin-3-y0oxy)propan-2- 2.06 (m, 1H), 1.72¨ 1.48 (m,
yl)oxy)pyridazin-3(2H)-one
5H), 1.29 (d, J = 6.3 Hz,
3H).
LCMS (ESI, m/z): 517.10
[M+H]+;
0 NH 11-1 NMR (300 MHz, DMS0-
I I d6) M3.22 (s, 1H), 8.70 (s,
oN
0
2H), 8.23 (s, 1H), 5.11 ¨4.99
47B (m, 1H), 4.82 (d, J= 13.4
/ cF3 Hz, 2H), 4.17 -3.99 (m, 2H),
3.98 ¨ 3.85 (m, 1H), 3.82 ¨
4-chloro-5-(((S)-1-(((R)-2-oxo-1-(1-(5-
(trifluoromethyppyrimidin-2-yOpiperidin-4- 3.74 (m, 1H), 3.27 ¨2.96 (m,
yOpyrrolidin-3-y0oxy)propan-2- 4H), 2.33 ¨ 2.18 (m, 1H),
yl)oxy)pyridazin-3(2H)-one
1.81 ¨ 1.49 (m, 5H), 1.29 (d,
J = 6.3 Hz, 3H).
0
Br
ytLNH
O 1\1
48A ".c-0 LCMS (ESI, m/z): 519.10
[M+H]+
/ CN
6-(4-((R)-3-((S)-2-((5-bromo-6-oxo-1,6-
dihydropyridazin-4-yl)oxy)propoxy)-2-
oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile
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Example
No. Structure Analytical Data
0
Br)(NH
I '
ON
48B 0 LCMS (ESI, m/z): 519.10
=N [M+H]+
¨011 j"-CN
6-(4-((S)-3-((S)-2-((5-bromo-6-oxo-1,6-
dihydropyridazin-4-yl)oxy)propoxy)-2-
oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile
0
F3C
NH
0
49A LCMS (ESI, m/z): 497.30
[MA41+
¨\\
5-(((S)-1-(((S)-1 -(1 -(5-methylpyrimidin-2-
yl)piperidin-4-y1)-2-oxopyrrolidin-3-
yl)oxy)propan-2-yl)oxy)-4-
(trifluoromethyl)pyridazin-3(2H)-one
0
F3C'A NH
oN
49B "".c--ON LCMS (ESI, m/z): 497.30
[M+H]+
N ----CN
N
5-(((S)-1-(((R)-1-(1-(5-methylpyrimidin-2-
yl)piperidin-4-y1)-2-oxopyrrolidin-3-
yl)oxy)propan-2-yl)oxy)-4-
(trifluoromethyl)pyridazin-3(2H)-one
Example 50: Synthesis of 6-(4-0R)-3-0S)-3-methoxy-2-06-oxo-5-(trifluoromethyl)-
1,6-
dihydropyridazin-4-yl)oxy)propoxy)-2-oxopyrrolidin-l-yl)piperidin-l-
yl)nicotinonitrile
and 6-(4-0S)-3-0S)-3-methoxy-2-06-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-
4-
yl)oxy)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile
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HCI
0 NH
A
HO
N CN
0
--0 OH
F3Cj=( N PMB
\--Otto I I
ON
CN
,0\ 0,1\¨o 0
0
0
F3o NNI H F3C:
ANH
\J
0
0
\--0,
/ CN
50B
50A
Step A
To a solution of 3-hydroxy-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride
(2.00 g,
9.06 mmol, 1.0 equiv) in DMF (8 mL) was added 6-chloronicotinonitrile (1.26 g,
9.09 mmol,
1.0 equiv) and K2CO3 (2.50 g, 18.1 mmol, 2.0 equiv). The resulting solution
was stirred for 2
hours at 80 C and then was quenched by the addition of water (20 mL). The
solution was
extracted with 2 x 50 mL of ethyl acetate. The organic layers were combined,
dried over
anhydrous sodium sulfate, and concentrated in vacuo. The crude product was
applied onto a
silica gel column eluting with ethyl acetate/petroleum ether (60/40) to afford
1.8 g (69%
yield) of 6-(4-(3-hydroxy-2-oxopyrrolidin-l-yl)piperidin-l-yl)nicotinonitrile
as a white solid.
(ES, m/z): 287.15 [M+H]+.
Step B
To a solution of 6-(4-(3-hydroxy-2-oxopyrrolidin-1-yl)piperidin-1-
yl)nicotinonitrile
(600 mg, 2.10 mmol, 1.0 equiv) in DMF (5 mL) was added NaH (334 mg, 8.35 mmol,
4.0
equiv, 60% dispersion in mineral oil) at 0 C. The solution was stirred for 10
min at 0 C, and
then (S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (650 mg, 2.51 mmol, 1.2
equiv) was
added. The solution was stirred for 25 hours at 50 C. Me0H (5 mL) was added,
and the
reaction was stirred for an additional 2 hours at 50 C. After concentration
the crude product
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was purified by reverse phase chromatography eluting with water/CH3CN (45/55)
to afford
300 mg (39% yield) of 6-(4-(3-((S)-2-hydroxy-3-methoxypropoxy)-2-oxopyrrolidin-
1-
yl)piperidin-1-yl)nicotinonitrile as a white solid. (ES, m/z): 375.25 [M+H]+.
Step C
To a solution of 6-(4-(3-((S)-2-hydroxy-3-methoxypropoxy)-2-oxopyrrolidin-1-
yl)piperidin-1-yl)nicotinonitrile (120 mg, 0.32 mmol, 1.0 equiv) in DCM (4 mL)
was added
5-chloro-2-(4-methoxybenzy1)-4-(trifluoromethyppyridazin-3(2H)-one (120 mg,
0.38 mmol,
1.2 equiv) and t-BuOK (72 mg, 0.64 mmol, 2.0 equiv). The resulting solution
was stirred for
2 hours and then concentrated in vacuo. The crude product was applied onto a
silica gel
column eluting with Me0H/DCM (8/92) to afford 160 mg (68% yield) of 6-(4-(3-
((S)-3-
methoxy-2-((1-(4-methoxybenzy1)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-
4-
yl)oxy)propoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile as a white
solid. LCMS
(ESI, m/z): 657.25 [M+Hr.
Step D
A solution of 6-(4-(3-((S)-3-methoxy-2-((1-(4-methoxybenzy1)-6-oxo-5-
(trifluoromethyl)-1,6-dihydropyridazin-4-y1)oxy)propoxy)-2-oxopyrrolidin-1-
y1)piperidin-1-
y1)nicotinonitrile (160 mg, 0.244 mmol, 1.00 equiv) in 1.2 ml of TFA and
triflic acid (5/1)
was stirred for 10 minutes at 0 C. The reaction was then quenched by addition
of water/ice
(10 mL). The pH of the solution was adjusted to ¨7-8 with saturated aqueous
Na2CO3. The
resulting solution was extracted with 3 x 50 mL of DCM. The organic layers
were combined
and concentrated in vacuo. The crude product was purified by reverse phase
chromatography,
and the isomeric mixture was separated by chiral prep HPLC: CHIRALPAK IA, 2*25
cm,5
p.m; Mobile Phase A: MTBE(10 mM NH3-MEOH), Mobile Phase B: Et0H; Flow rate:16
mL/min; Gradient: 30 % B for 15 min; 220/254 nm to afford the separated
compounds. The
relative stereochemistry of compounds was assigned by analogy to Example 10,
based on the
PARP7 potency of the more active diastereomer and in analogy to the Example
10B X-ray
crystal structure.
Example 50 Isomer A (50A): 6-(4-((S)-3-((S)-3-methoxy-2-((6-oxo-5-
(trifluoromethyl)-
1,6-dihydropyridazin-4-yl)oxy)propoxy)-2-oxopyrrolidin-1-y1)piperidin-1-
y1)nicotinonitrile
(46 mg, 35% yield, white solid). LCMS (ESI, m/z): 537.15[M+H]+; 1FINMR (300
MHz,
DMSO-d6) 6 13.21 (s, 1H), 8.45 (d, J = 2.3 Hz, 1H), 8.27 (s, 1H), 7.80 (dd, J
= 9.1, 2.4 Hz,
1H), 6.94 (d, J = 9.1 Hz, 1H), 5.21 (br, 1H), 4.52 (d, J = 13.4 Hz, 2H), 4.09
¨ 3.96 (m, 3H),
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3.77-3.64 (m, 1H), 3.62-3.47 (m, 2H), 3.26(s,3H), 3.23 - 3.04 (m, 2H), 3.02-
2.89 (m, 2H),
2.25 -2.11 (m, 1H), 1.69-1.46 (m, 5H). CHIRALPAK IA-3, 4.6*100 mm 3 p.m;
Mobile Phase
A: MtBE (0.1% Diethyl amine): Et0H = 75:25; Flow rate:1 mL/min; Retention
time:
1.589min (faster peak).
Example 50 Isomer A (50B): 6-(4-((R)-3-((S)-3-methoxy-2-46-oxo-5-
(trifluoromethyl)-1,6-
dihydropyridazin-4-y0oxy)propoxy)-2-oxopyrrolidin-1-y1)piperidin-1-
y1)nicotinonitrile (54
mg, 41% yield, white solid). LCMS (ESI, m/z): 537.15[M+H]+, IIINMR (300 MHz,
DMSO-
d6) 6 13.21 (s, 1H), 8.45 (d, J = 2.4 Hz, 1H), 8.29 (s, 1H), 7.80 (dd, J =
9.1, 2.4 Hz, 1H), 6.94
(d, J = 9.1 Hz, 1H), 5.21 (br, 1H), 4.52 (d, J = 13.3 Hz, 2H), 4.11-3.87 (m,
3H), 3.85-3.75 (m,
1H), 3.64 -3.47 (m, 2H), 3.25 (s,3H),3.24 -2.87 (m, 4H), 2.27 -2.13 (m, 1H),
1.76 -1.47 (m,
5H). CHIRALPAK IA-3, 4.6*100 mm 3 p.m; Mobile Phase A: MtBE (0.1% Diethyl
amine):Et0H=75:25; Flow rate:1 mL/min; Retention time: 1.992 min (slower
peak).
Examples 51-52
Examples 51-52 were synthesized according to the procedures described for the
synthesis of 6-(4-((R)-3-((S)-3-methoxy-2-46-oxo-5-(trifluoromethyl)-1,6-
dihydropyridazin-
4-y1)oxy)propoxy)-2-oxopyrrolidin-1-y1)piperidin-1-y1)nicotinonitrile and 6-(4-
((S)-3-((S)-3-
methoxy-2-46-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-ypoxy)propoxy)-2-
oxopyrrolidin-1-yOpiperidin-1-yOnicotinonitrile (see Example 50) using
appropriate building
blocks and modified reaction conditions (such as reagent ratio, temperature,
coupling
conditions, and reaction time) as needed. The relative stereochemistry of
compounds was
assigned by analogy to Example 10, based on the PARP7 potency of the more
active
diastereomer and in analogy to the Example 10B X-ray crystal structure.
Example
No. Structure Analytical Data
F3c,A
r
0
51A LCMS (ESI, m/z): 581.20
[M+H]+
5-(((S)-1-methoxy-3-(((S)-2-oxo-1-(1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-
yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-
(trifluoromethyl)pyridazin-3(2H)-one
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Example
No. Structure Analytical Data
F3c,A
r
¨N4
51B LCMS (ESI, m/z): 581.20
N [M+H]+
5-(((S)-1-methoxy-3-(((R)-2-oxo-1-(1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-
yl)pyrrolidin-3-y0oxy)propan-2-y0oxy)-4-
(trifluoromethyl)pyridazin-3(2H)-one
0
F30,)(
r
,0
52A
LCMS (ESI, m/z): 527.20
dN
[M+H]+
5-(((S)-1-methoxy-3-(((S)-1-(1-(5-
methylpyrimidin-2-yl)piperidin-4-y1)-2-
oxopyrrolidin-3-y0oxy)propan-2-y0oxy)-4-
(trifluoromethyl)pyridazin-3(2H)-one
0
F30)L
r
_o
52B
LCMS (ESI, m/z): 527.15
5-(((S)-1-methoxy-3-(((R)-1-(1-(5-
methylpyrimidin-2-yl)piperidin-4-y1)-2-
oxopyrrolidin-3-y0oxy)propan-2-y0oxy)-4-
(trifluoromethyl)pyridazin-3(2H)-one
Examples 53 and 54
Examples 53 and 54 were synthesized according to the procedures described for
the
synthesis of 6-(4-((S)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-
dihydropyridazin-
4-yl)amino)propoxy)-2-oxopyrrolidin-1-y1)piperidin-1-y1)nicotinonitrile and 6-
(4-((R)-3-((S)-
3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-
yl)amino)propoxy)-2-
oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile (see Examples 17A and 17B)
using
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appropriate building blocks and modified reaction conditions (such as reagent
ratio,
temperature, coupling conditions, and reaction time) as needed.
Example
Structure Analytical Data
No.
0
F3CNH
I I
HNN
,c,\µµµ.0
53
LCMS (ESI, m/z): 526.30
[M+H]+
5-(((S)-1-methoxy-3-(((R)-1-(1-(5-
methylpyrimidin-2-yl)piperidin-4-y1)-2-
oxopyrrolidin-3-y0oxy)propan-2-y0amino)-4-
(trifluoromethyppyridazin-3(2H)-one
LCMS (ESI, m/z): 542.20
[M+H]+;11-INMR (300
0
F3C MHz, DMSO-d6) 6 12.49 (s,
i N111-1
HNN 1H), 7.97 (d, J= 14.5 Hz,
2H), 6.28 (br, 1H), 4.30 (br,
54
1H), 4.11 - 3.95 (m, 4H),
3.70 - 3.58 (m, 3H), 3.48 (d,
2-(4-((R)-3-((S)-3-methoxy-2-((6-oxo-5- J= 5.2 Hz, 3H), 3.27 - 3.22
(
(trifluoromethyl)-1,6-dihydropyridazin-4-
yl)amino)propoxy)-2-oxopyrrolidin-1- m, 3H), 3.18 ¨3.06 (m, 2H),
yl)piperidin-1-yl)thiazole-5-carbonitrile 2.25 (br, 1H), 1.78 ¨ 1.62
(m,
5H).
Example 55: Synthesis of 6-(4-((R)-3-((S)-2-((5-bromo-6-oxo-1,6-
dihydropyridazin-4-
yl)oxy)-3-methoxypropoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile
and 6-(4-
((S)-3-((S)-2-((5-bromo-6-oxo-1,6-dihydropyridazin-4-yl)oxy)-3-methoxypropoxy)-
2-
oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile
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0
-0 OH BrN,PMB
I I
\--Otto 0
A
CN
0 0
Br
Br
ajH
0 A\J
0
_________________ --0\0) 0
\--0, 0
,d
CN
55A 55B
Step A
To a solution of 6-(4-(3-((S)-2-hydroxy-3-methoxypropoxy)-2-oxopyrrolidin-1-
yl)piperidin-1-yl)nicotinonitrile (280 mg, 0.75 mmol, 1.0 equiv) at 0 C in
DMF (3 mL) was
.. added NaH (60 mg, 1.50 mmol, 2.01 equiv, 60% dispersion in mineral oil).
The mixture was
stirred for 10 min at 0 C and then 4,5-dibromo-2-(4-methoxybenzyl)pyridazin-
3(2H)-one
(330 mg, 0.88 mmol, 1.2 equiv) was added, and the resulting solution stirred
for 1 hour at
room temperature. The reaction was then quenched with saturated aqueous NH4C1
(0.5 mL),
and the resulting mixture was concentrated. The crude product was purified by
reverse phase
column eluting with water/CH3CN (65/45) to afford 150 mg (30% yield) of 6-(4-
(3-((S)-2-
((5-bromo-1-(4-methoxybenzy1)-6-oxo-1,6-dihydropyridazin-4-y0oxy)-3-
methoxypropoxy)-
2-oxopyrrolidin-1-yOpiperidin-1-yOnicotinonitrile as a yellow solid. (ES,
m/z): 669.30
[M+H]+.
Step B
A solution of 6-(4-(3-((S)-2-((5-bromo-1-(4-methoxybenzy1)-6-oxo-1,6-
dihydropyridazin-4-yl)oxy)-3-methoxypropoxy)-2-oxopyrrolidin-1-y1)piperidin-1-
y1)nicotinonitrile (150 mg, 0.23 mmol, 1.0 equiv) in 1:5 Tf0H/TFA (1.5 mL) was
stirred for
15 min at room temperature. The resulting solution was diluted with water (15
mL), and the
pH was adjusted to 7-8 with sodium bicarbonate solution. The solution was
extracted with 3 x
50 mL of DCM. The organic layers were combined, dried over anhydrous sodium
sulfate and
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concentrated. The crude product was purified by reverse phase chromatography
eluting with
water/CH3CN, and the isomeric mixture was separated by chiral prep HPLC:
CHIRAL ART
Cellulose-SB, 2*25 cm, 5 p.m; Mobile Phase A: MTBE(10 mM NH3-MEOH), Mobile
Phase
B: Et0H; Flow rate: 20 mL/min; Gradient: 20% B for 15 min; 220/254 nm. The
relative
.. stereochemistry of compounds was assigned by analogy to Example 10, based
on the PARP7
potency of the more active diastereomer and in analogy to the Example 10B X-
ray crystal
structure.
Example 55 Isomer A (55A): 6-(4-((S)-3-((S)-2-((5-bromo-6-oxo-1,6-
dihydropyridazin-4-
y0oxy)-3-methoxypropoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile
(31 mg, 25%
yield, white solid). LCMS (ESI, m/z): 549.10 [M+H1+; 1H NMR (400 MHz, DMSO-d6)
6
13.13 (s, 1H), 8.47 (s, 1H), 8.11 (s, 1H), 7.83 (d, J = 9.1 Hz, 1H), 6.96 (d,
J = 9.1 Hz, 1H),
5.08 (br, 1H), 4.59-4.48 (m, 2H), 4.12-3.95 (m, 3H), 3.79-3.70 (m, 1H), 3.65-
3.54 (m, 2H),
3.29 (s,3H),3.25-3.06 (m, 2H), 3.04-2.91 (m, 2H), 2.27-2.15 (m, 1H), 1.72-1.46
(m, 5H).
Chiral HPLC: Column: CHIRAL ART Cellulose-SB, 4.6*100 mm, 3 um; Mobile Phase:
MtBE(0.1% diethyl amine):Et0H=80:20; Flow rate: 1 mL/min. Retention time:
3.928 min
(faster peak).
Example 55 Isomer A (55B): 6-(4-((R)-3-((S)-2-((5-bromo-6-oxo-1,6-
dihydropyridazin-4-
yl)oxy)-3-methoxypropoxy)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile
(42 mg, 35%
yield, white solid). LCMS (ESI, m/z): 549.15 [M+H1+; 1H NMR (400 MHz, DMSO-d6)
6
.. 13.14 (s, 1H), 8.47 (s, 1H), 8.13 (s, 1H), 7.85 (d, J = 9.2 Hz, 1H), 6.96
(d, J = 9.2 Hz, 1H),
5.08 (br, 1H), 4.57 ¨ 4.49 (m, 2H), 4.14-3.91 (m, 3H), 3.86-3.79 (m, 1H), 3.65-
3.53 (m, 2H),
3.29 (s, 3H), 3.25-3.07 (m, 2H), 3.05-2.92 (m, 2H), 2.34-2.19(m,1H),1.78 ¨
1.46 (m, 5H).
Chiral HPLC: Column: CHIRAL ART Cellulose-SB, 4.6*100 mm, 3 p.m; Mobile Phase:
MtBE(0.1% diethyl amine):Et0H = 80:20; Flow rate: 1 mL/min. Retention time:
4.384 min
.. (slower peak).
Example 56
Example 56 was synthesized according to the procedures described for the
synthesis
of 6-(4-((R)-3-((S)-2-((5-bromo-6-oxo-1,6-dihydropyridazin-4-yl)oxy)-3-
methoxypropoxy)-
2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinonitrile and 6-(4-((S)-3-((S)-2-((5-
bromo-6-oxo-
1,6-dihydropyridazin-4-yl)oxy)-3-methoxypropoxy)-2-oxopyrrolidin-1-
y1)piperidin-1-
y1)nicotinonitrile (see Example 55) using appropriate building blocks and
modified reaction
conditions (such as reagent ratio, temperature, coupling conditions, and
reaction time) as
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needed. The relative stereochemistry of compounds was assigned by analogy to
Example 10,
based on the PARP7 potency of the more active diastereomer and in analogy to
the Example
10B X-ray crystal structure.
Example
Structure Analytical Data
No.
0
Br
0 0
56A LCMS (ESI, m/z): 593.10
J-CF3
[M+H]+
4-Bromo-5-(((S)-1-methoxy-3-(((S)-2-oxo-1-
(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-
4-yl)pyrrolidin-3-y0oxy)propan-2-
yl)oxy)pyridazin-3(2H)-one
0
Br.).LNH
I I
0 0
56B
LCMS (ESI, m/z): 593.10
N-0\14NXCF3
[M+H]+
4-Bromo-5-(((S)-1-methoxy-3-(((R)-2-oxo-1-
(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-
4-yl)pyrrolidin-3-y0oxy)propan-2-
yl)oxy)pyridazin-3(2H)-one
Example 57: Synthesis of 5-0(S)-1-0(R)-1-03R,4R)-3-hydroxy-1-(5-
(trifluoromethyppyrimidin-2-yl)piperidin-4-y1)-2-oxopyrrolidin-3-yl)oxy)propan-
2-
yl)amino)-4-(trifluoromethyppyridazin-3(2H)-one
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BOG-NH H2N HCI.
-:
Boc-NH HO...-0 HO.-0 C
-.
HO A B N ___________ ...
N _______________________________________
.-0 _______
),--N Nq
NH Nq
CF3
CF3
Boc
NH
HO......
0
H2N, LO
TBS0.(, ..--\
)......0
D E
F
TBSO":01 _________________________________________ .- ._-N,.
_,..
TBSO"NyN
Nq
N\......_____Z
NI,.
CF3 CF3 CF3
0
0 F3C
NH2
F3CN,PMB tjEl
,N
w=c_
HN
HCI HN I '
,N
'DU G __ "µ.c--00 H
N '''N---(:)--CF3
HO'.1. N' CF3 c N-e_-
N / CF3 HO N
HO
Step A
To a solution of tert-butyl ((3R,4R)-3-hydroxypiperidin-4-yl)carbamate (980
mg, 4.53
mmol, 1.0 equiv) in DMF (5 mL) was added 2-chloro-5-
(trifluoromethyl)pyrimidine (825
mg, 4.52 mmol, 1.0 equiv) and K2CO3 (940 mg, 6.80 mmol, 1.5 equiv). The
resulting
solution stirred for 1 hour at 50 C and then was quenched by the addition of
water (15 mL).
The solids were collected by filtration to afford 1.6 g (97% yield) of tert-
butyl ((3R,4R)-3-
hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)carbamate as a
white solid.
(ESI, m/z): 363.10 [M+H1+.
Step B
A solution of tert-butyl ((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-yl)carbamate (1.60 g, 4.42 mmol, 1.0 equiv) in 4M HC1 in 1,4-
dioxane (30
mL) was stirred for 1 hour at 40 C. The resulting mixture was concentrated in
vacuo to
afford 1.1 g (95% yield) of (3R,4R)-4-amino-1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-
3-ol hydrochloride as a white solid. (ESI, m/z): 263.05 [M+H1+.
Step C
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To a solution of (3R,4R)-4-amino-1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-3-ol
hydrochloride (980 mg, 3.74 mmol, 1.0 equiv) in CH3CN (30 mL) was added
imidazole (1.27
g, 18.7 mmol, 5.0 equiv) and tert-butylchlorodimethylsilane (1.69 g, 11.2
mmol, 3.0 equiv).
The resulting solution was stirred for 30 hours at 60 C. After filtration,
the filtrate was
concentrated in vacuo, and the crude product was applied onto a silica gel
column eluting
with Me0H/DCM (3:97) to afford 1.3 g (92% yield) of (3R,4R)-3-((tert-
butyldimethylsily0oxy)-1-(5-(trifluoromethyppyrimidin-2-yOpiperidin-4-amine as
a yellow
oil. (ESI, in/z): 377.4 [M+H1+.
Step D
To a solution of (3R,4R)-3-((tert-butyldimethylsily0oxy)-1-(5-
(trifluoromethyppyrimidin-2-yOpiperidin-4-amine (1.28 g, 3.40 mmol, 1.0 equiv)
in DCM
(20 mL) was added (R)-2-(2,2-dimethy1-5-oxo-1,3-dioxolan-4-yOacetaldehyde
(1.88 g, 11.9
mmol, 3.5 equiv) and AcOH (408 mg, 6.79 mmol, 2.0 equiv). The resulting
solution was
stirred for 1 hour. STAB (2.16 g, 10.2 mmol, 3.0 equiv) was added, and the
solution was
.. stirred for an additional 4 hours. The reaction was quenched by the
addition of saturated
aqueous NaHCO3. The aqueous layers were extracted with 2 x 50 mL of DCM. The
organic
layers were combined, dried over anhydrous sodium sulfate and concentrated in
vacuo. The
crude product was applied onto a silica gel column eluting with ethyl
acetate/petroleum ether
(35/65) to afford 680 mg (43% yield) of (R)-1-((3R,4R)-3-((tert-
butyldimethylsily0oxy)-1-
(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-y1)-3-hydroxypyrrolidin-2-one
as a white
solid. (ESI, m/z): 461.20 [M+H1+.
Step E
To a solution of (R)-1-43R,4R)-3-((tert-butyldimethylsily0oxy)-1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-y1)-3-hydroxypyrrolidin-2-one (670
mg, 1.46
.. mmol, 1.00 equiv) in DMF (7 mL) at 0 C was added NaH (117 mg, 2.93 mmol,
2.01 equiv,
60% dispersion in mineral oil). The resulting solution was stirred for 10 min,
and then tert-
butyl (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (518 mg,
2.18 mmol, 1.5
equiv) was added, and the solution was maintained at the same temperature for
4 hours. The
reaction was then quenched by the addition of saturated aqueous NH4C1. The
solution was
.. extracted with 2 x 50 mL of ethyl acetate. The organic layers were
combined, dried over
anhydrous sodium sulfate and concentrated. The crude product was applied onto
a silica gel
column eluting with ethyl acetate/petroleum ether (3/2) to afford 300 mg (33%
yield) of tert-
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butyl ((S)-1-4(R)-1-43R,4R)-3-((tert-butyldimethylsily0oxy)-1-(5-
(trifluoromethyppyrimidin-2-yOpiperidin-4-y1)-2-oxopyrrolidin-3-y0oxy)propan-2-
yOcarbamate as a yellow solid. (ESI, m/z): 618.30 [M+Hr.
Step F
A solution of tert-butyl ((S)-1-(((R)-1-43R,4R)-3-((tert-
butyldimethylsily0oxy)-1-(5-
(trifluoromethyppyrimidin-2-yOpiperidin-4-y1)-2-oxopyrrolidin-3-y0oxy)propan-2-
yOcarbamate (290 mg, 0.47 mmol, 1.0 equiv) in 4N HC1 in 1,4-dioxane (20 mL)
was stirred
for 15 hours. The resulting mixture was concentrated to afford 240 mg of (R)-3-
((S)-2-
aminopropoxy)-1-((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-
yl)pyrrolidin-2-one hydrochloride as a white solid that was carried forward
without further
purification. (ESI, m/z): 404.15 [M+H]+.
Step G
To a solution of (R)-3-((S)-2-aminopropoxy)-1-((3R,4R)-3-hydroxy-1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride
(230 mg, 0.57
mmol, 1.0 equiv) in Et0H (4 mL) was added 5-chloro-2-(4-methoxybenzy1)-4-
(trifluoromethyl)pyridazin-3(2H)-one (181 mg, 0.57 mmol, 1.0 equiv) and
triethylamine (173
mg, 1.71 mmol, 3.0 equiv). The resulting solution was stirred for 1 hour at 60
C. After
completion, the crude product was applied onto a reverse phase column eluting
with
water/CH3CN (45/55) to afford 185 mg (47% yield) of 5-(((S)-1-(((R)-1-((3R,4R)-
3-hydroxy-
1-(5 -(trifluoromethyl)pyri mi din-2-yl)piperi din-4-y1)-2-oxopy rroli din-3 -
yl)oxy)prop an-2-
yl)amino)-2-(4-methoxybenzy1)-4-(trifluoromethyl)pyridazin-3(2H)-one as a
white solid.
(ESI, m/z): 686.25 [M+I-11+.
Step H
A solution of 5-(((S)-1-(((R)-1-((3R,4R)-3-hydroxy-1-(5-
(trifluoromethyppyrimidin-
2-yOpiperidin-4-y1)-2-oxopyrrolidin-3-y0oxy)propan-2-y0amino)-2-(4-
methoxybenzyl)-4-
(trifluoromethyl)pyridazin-3(2H)-one (185 mg, 0.270 mmol, 1.0 equiv) in TFA
(1.5 mL) and
TfOH (0.3 mL) was stirred for 1 hour. The reaction was quenched by the
addition of ice
water (2 mL). The pH was adjusted to ¨7-8 with saturated aqueous Na2CO3. The
resulting
solution was extracted with 2 x 50 mL of DCM. The organic layers were combined
and
concentrated. The crude product was purified by reverse phase chromatography
eluting with
water/CH3CN (45/55) to afford 89 mg (59% yield) of 5-(((S)-1-(((R)-1-((3R,4R)-
3-hydroxy-
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1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-y1)-2-oxopyrrolidin-3-
yl)oxy)propan-2-
yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one as a white solid. (ESI, m/z):
566.15
[M+H1+; 1H NMR (300 MHz, DMSO-d6) 6 12.46 (s, 1H), 8.69 (d, J= 0.9 Hz, 2H),
7.94 (s,
1H), 6.39-6.29 (m, 1H), 5.28 (d, J= 5.3 Hz, 1H), 4.91-4.80 (m, 1H), 4.72 (d,
J= 13.4 Hz,
1H), 4.21-4.07 (m, 2H), 3.84-3.73 (m, 2H), 3.63-3.49 (m, 2H), 3.29-3.22 (m,
1H), 3.17-3.07
(m, 1H), 3.02-2.89 (m, 1H), 2.84-2.70 (m,1H), 2.31-2.16 (m, 1H), 1.83-1.68 (m,
1H), 1.65-
1.48 (m, 2H), 1.16 (d, J= 6.4 Hz, 3H).
Example 58: Synthesis of 5-4(S)-1-4(R)-1-43S,4S)-3-hyd roxy-1-(5-
(trifluoromethyppyrimidin-2-yl)piperidin-4-y1)-2-oxopyrrolidin-3-yl)oxy)prop
an-2-
yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
HCI
Boc-NH H2N
Boc-NH HO' =o HO' .a
A B N C
HO 1 = --.-) __ N ___________________________ ..
),--N
NH Nq Nq
CF3 CF3
Boc
HO 0
...... ,..
cAr\I 0 (NH
--..
H2N 0
).......,D
TBS01..a N E F
D __________________________________________________________________ .
________________________________ TBSO"n
)/--N )7--\
N_)N\...,.._....Z TBSO".c.-Ni.....a
0F3 0F3 Ni
0F3
0
NH2 0
HCI F3CAN,PMB F3C
tiEl
0
HN N
-,..r0 HN
=c__ 0
G ok-o 0 H os0
H0"01 N
= -\\ / CF3 N
'0.--iND-C F3
N
HN2,1 Hd N Hd
CF3
Step A
To a solution of tert-butyl ((3S,4S)-3-hydroxypiperidin-4-yl)carbamate (1.00
g, 4.62
mmol, 1.0 equiv) in DMF (5 mL) was added K2CO3 (0.96 g, 6.95 mmol, 1.5 equiv)
and 2-
chloro-5-(trifluoromethyl)pyrimidine (0.85 g, 4.66 mmol, 1.0 equiv). The
resulting solution
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was stirred for 1 hour at 50 C. The reaction mixture was quenched by the
addition of 10 mL
of water, and the solids were collected by filtration to afford 1.45 g (87%
yield) of tert-butyl
((3S,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-
yl)carbamate as a white
solid. LCMS (ESI, m/z): 363.10 [M+Hr.
Step B
A solution of tert-butyl ((3S,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-yl)carbamate (1.45 g, 4.00 mmol, 1.0 equiv) in 4N HC1 in 1,4-
dioxane (30 mL)
was stirred for 2 hours at 40 C. The resulting mixture was concentrated to
afford 1.0 g (95%
yield) of (3S,4S)-4-amino-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-3-ol
hydrochloride
as a yellow solid. LCMS (ESI, m/z): 263.05 [M+H1+.
Step C
To a solution of (3S,4S)-4-amino-1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-3-ol
hydrochloride (1.19 g, 3.98 mmol, 1.0 equiv) in CH3CN (40 mL) was added tert-
butyldimethylsily1 chloride (2.36 g, 15.7 mmol, 3.93 equiv) and imidazole
(1.77 g, 26.0
mmol, 6.5 equiv). The resulting solution was stirred overnight at 60 C. After
filtration, the
filtrate was concentrated in vacuo, and the crude product was applied onto a
silica gel column
eluting with chloroform/methanol (10/1) to afford 1.20 g (80% yield) of
(3S,4S)-3-(ftert-
butyldimethylsily0oxy)-1-(5-methylpyrimidin-2-yOpiperidin-4-amine as a white
solid.
LCMS (ESI, m/z): 377.10 [M+1-11+
Step D
To a solution of (35,4S)-3-(ftert-butyldimethylsily0oxy)-1-(5-methylpyrimidin-
2-
yOpiperidin-4-amine (1.40 g, 3.72 mmol, 1.0 equiv) in DCM (20 mL) was added
(R)-2-(2,2-
dimethy1-5-oxo-1,3-dioxolan-4-yOacetaldehyde (1.88 g, 11.9 mmol, 3.2 equiv)
and AcOH
(446 mg, 7.44 mmol, 2.0 equiv). After stirring for 15 min, STAB (2.36 g, 11.2
mmol, 3.0
equiv) was added, and the solution was stirred for an additional 5 hours. The
reaction was
quenched by the addition of 20 mL of saturated aqueous NaHCO3 and extracted
with 3 x 50
mL of DCM. The organic layers were combined, dried over anhydrous sodium
sulfate and
concentrated in vacuo. The crude product was applied onto a silica gel column
eluting with
ethyl acetate/petroleum ether (3/2) to afford 470 mg (27% yield) of (R)-1-
435,45)-3-((tert-
butyldimethylsilyl)oxy)-1-(5-ftrifluoromethyppyrimidin-2-yOpiperidin-4-y1)-3-
hydroxypyrrolidin-2-one as a yellow solid. LCMS (ESI, m/z): 461.20 [M+Hr.
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Step E
To a solution of (R)-1-((3S,4S)-3-((tert-butyldimethylsily0oxy)-1-(5-
(trifluoromethyppyrimidin-2-yOpiperidin-4-y1)-3-hydroxypyrrolidin-2-one (465
mg, 1.01
mmol, 1.0 equiv) in DMF (5 mL) was added NaH (121 mg, 3.03 mmol, 3.0 equiv,
60%) at 0
C. The reaction mixture was stirred for 10 min, and then a solution of tert-
butyl (S)-4-
methy1-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (287 mg, 1.21 mmol, 1.2
equiv) in
DMF (2 mL) was added. The resulting solution was stirred for 2 hours at 0 C.
The reaction
was quenched by the addition of water (10 mL). The resulting solution was
extracted with 2 x
20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous
sodium
sulfate and concentrated in vacuo. The crude product was applied onto a silica
gel column
eluting with ethyl acetate/petroleum ether (3/2) to afford 480 mg (77% yield)
of tert-butyl
((S)-1-(((R)-1-((3S,4S)-3-((tert-butyldimethylsily0oxy)-1-(5-
(trifluoromethyppyrimidin-2-
yOpiperidin-4-y1)-2-oxopyrrolidin-3-y1)oxy)propan-2-y1)carbamate as a yellow
solid. LCMS
(ESI, m/z): 618.35 [M+Hr.
Step F
A solution of tert-butyl ((S)-1-4(R)-1-43S,4S)-3-((tert-butyldimethylsily0oxy)-
1-(5-
(trifluoromethyppyrimidin-2-yOpiperidin-4-y1)-2-oxopyrrolidin-3-y0oxy)propan-2-
yOcarbamate (480 mg, 0.78 mmol, 1.0 equiv) in 4M HC1 in 1,4-dioxane (10 mL, 4
M) was
stirred for 1 hour at room temperature. The resulting mixture was concentrated
in vacuo to
.. afford 278 mg (81% yield) of (R)-3-((S)-2-aminopropoxy)-1-((3S,4S)-3-
hydroxy-1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride
as a white
solid. (ESI, m/z): 461.25 [M+H1+.
Step G
To a solution of (R)-3-((S)-2-aminopropoxy)-1-((3S,4S)-3-hydroxy-1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride
(270 mg, 0.61
mmol, 1.0 equiv) in Et0H (8 mL) was added 5-chloro-2-(4-methoxybenzy1)-4-
(trifluoromethyl)pyridazin-3(2H)-one (293 mg, 0.92 mmol, 1.5 equiv) and
triethylamine (621
mg, 6.14 mmol, 10.0 equiv). The resulting solution was stirred for 3 hours at
60 C and then
was concentrated in vacuo. The crude product was applied onto a silica gel
column eluting
.. with ethyl acetate/petroleum ether (7/3) to afford 280 mg (67% yield) of 5-
(((S)-1-(((R)-1-
((3S,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-y1)-2-
oxopyrrolidin-3-
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yl)oxy)propan-2-y0amino)-2-(4-methoxybenzyl)-4-(trifluoromethyppyridazin-3(2H)-
one as
a yellow solid. LCMS (ESI, m/z): 686.20 [M+1-11+.
Step H
A solution of 5-(((S)-1-(((R)-1-((3S,4S)-3-hydroxy-1-(5-
(trifluoromethyppyridin-2-
yOpiperidin-4-y1)-2-oxopyrrolidin-3-y0oxy)propan-2-y0amino)-2-(4-
methoxybenzyl)-4-
(trifluoromethyppyridazin-3(2H)-one (270 mg, 0.39 mmol, 1.0 equiv) in
Tf0H/TFA=1:10 (3
mL) was stirred for 2 hours at 0 C. The reaction was quenched by the addition
of water (5
mL), and the pH was adjusted to 7-8 with aqueous sodium bicarbonate. The
resulting solution
was extracted with 3 x 20 mL of ethyl acetate. The organic layers were
combined, dried over
anhydrous sodium sulfate and concentrated. The crude product was purified by
reverse phase
chromatography eluting with water/CH3CN (1/1) to afford 120 mg (54% yield) of
5-(((S)-1-
(((R)-1-((3S,4S)-3-hydroxy-1-(5-(trifluoromethyppyrimidin-2-yOpiperidin-4-y1)-
2-
oxopyrrolidin-3-y0oxy)propan-2-y0amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
as an
off-white solid. LCMS (ESI, m/z): 566.20 [M+Hr. 1FINMR (400 MHz, DMSO-d6) 6
12.46
(s, 1H), 8.70 (s, 2H), 7.95 (s, 1H), 6.35 - 6.34 (m, 1H), 5.26 (d, J= 5.0 Hz,
1H), 4.91 ¨ 4.83
(m, 1H), 4.80 - 4.75 (m, 1H), 4.28 -4.10 (m, 2H), 3.80 - 3.91(m, 2H), 3.63 -
3.58(m, 1H),
3.55 -3.40 (m, 1H), 3.31 - 3.25(m, 1H), 3.22 ¨ 3.12 (m, 1H), 3.06 ¨ 2.95 (m,
1H), 2.81 - 2.76
(m, 1H), 2.33 - 2.20 (m, 1H), 1.78 - 1.66 (m, 1H), 1.64- 1.51(m, 2H), 1.17 (d,
J= 6.4 Hz,
3H).
Example 59: Synthesis of 5-0(S)-1-0(R)-1-03S,4R)-3-hydroxy-1-(5-
(trifluoromethyppyrimidin-2-yl)piperidin-4-y1)-2-oxopyrrolidin-3-yl)oxy)propan-
2-
yl)amino)-4-(trifluoromethyppyridazin-3(2H)-one
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HCI
H2N,
Boc . __
HN, HO' - C
Boc-NJ-I A B N C
__________________________________ - HO"' 0, ,
HO," \--...:_z \
N
QH )7
N
CF3
CF3
H2N,. HO._..... Boc,
0 NH
TBSOI ,=C
N D ) E F __ .-
' TBSO"' a _________________________________ ' ---t, ,---1
N\ ____________
N
sk_,., ALAõ,N)
N TBSOs
CF3
IN ---.---CF
CF3 3
NH2
""=( HCI
0
LO 0
)....0 G F3CAN- H N
PMB F3CJOH
\---N,
HN NI 0
, HN
HO" N ,.Ø...N,..CN___P-M--µ j CF3 N -µ,
Step A
To a solution of tert-butyl ((3S,4R)-3-hydroxypiperidin-4-yl)carbamate (2.00
g, 9.2
mmol, 1.0 equiv) in DMF (10 mL) was added 2-chloro-5-
(trifluoromethyl)pyrimidine (1.68
g, 9.2 mmol, 1.00 equiv) and K2CO3 (2.56 g, 18.5 mmol, 2.0 equiv). The
resulting solution
was stirred for 1 hour at 50 C then diluted with water (10 mL). The solids
were collected by
filtration to afford 1.37 g (39% yield) of tert-butyl ((3S,4R)-3-hydroxy-1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)carbamate as a white solid.
LCMS (ESI, m/z):
363.10 [M+H1+.
.. Step B
A solution of tert-butyl ((3S,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-yl)carbamate (1.28 g, 3.53 mmol, 1.0 equiv) in 4M HC1 in
dioxane (6 mL) was
stirred for 2 hours. The resulting mixture was concentrated in vacuo to afford
1.0 g (95%
yield) of (3S,4R)-4-amino-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-3-ol
hydrochloride
as a yellow solid. LCMS (ESI, m/z): 263.05 [M+1-11+.
Step C
To a solution of (3S,4R)-4-amino-1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-3-ol
hydrochloride (2.60 g, 9.92 mmol, 1.0 equiv) in CH3CN (20 mL) was added tert-
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butyldimethylsilyl chloride (11.95 g, 79.35 mmol, 8.0 equiv) and imidazole
(5.40g, 79.4
mmol, 8.0 equiv). The resulting solution was stirred for 4 hours at 60 C and
then was
concentrated in vacuo. The crude product was applied onto a silica gel column
eluting with
chloroform/methanol (9/1) to give 3.40 g (88% yield) of (3S,4R)-3-((tert-
butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-amine
as a yellow
solid. LCMS (ESI, m/z): 377.10 [M+Hr
Step D
To a solution of (3S,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-amine (3.20 g, 8.50 mmol, 1.0
equiv) in DCM
(30 mL) was added (R)-2-(2,2-dimethy1-5-oxo-1,3-dioxolan-4-yOacetaldehyde
(1.24 g, 7.82
mmol, 0.9 equiv) and AcOH (1.53 g, 25.5 mmol, 3.0 equiv). The resulting
solution was
stirred for 15 min, and then STAB (14.0 g, 66.0 mmol, 3.0 equiv) was added.
After 2 hours
at, the reaction was quenched by the addition of 20 mL of saturated aqueous
NaHCO3. The
solution was extracted with 3 x 100 mL of DCM. The organic layers were
combined, dried
over anhydrous sodium sulfate and concentrated in vacuo. The crude product was
applied
onto a silica gel column eluting with ethyl acetate/petroleum ether (3/1) to
afford 0.93 g (24%
yield) of (R)-1-((3S,4R)-3-((tert-butyldimethylsily0oxy)-1-(5-
(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-y1)-3-hydroxypyrrolidin-2-one as a yellow solid. LCMS (ESI,
m/z): 461.20
[M+H]+.
Step E
To a solution of (R)-1-((35,4R)-3-((tert-butyldimethylsily0oxy)-1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-y1)-3-hydroxypyrrolidin-2-one (920
mg, 2.0
mmol, 1.0 equiv) in DMF (8 mL) was slowly added NaH (239 mg, 5.99 mmol, 3.0
equiv,
60% dispersion in mineral oil) at 0 C over the course of 10 min. tert-Butyl
(S)-4-methyl-
1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (568 mg, 2.40 mmol, 1.2 equiv)
was then
added, and the resulting solution stirred for 2 hours at 0 C. The reaction
was quenched by the
addition of water (10 mL) and was extracted with 2 x 30 mL of ethyl acetate.
The organic
layers were combined, dried over anhydrous sodium sulfate and concentrated in
vacuo. The
crude product was applied onto a silica gel column eluting with ethyl
acetate/petroleum ether
(3/2) to afford 767 mg (62% yield) of tert-butyl ((S)-1-4(R)-1-435,4R)-3-
((tert-
butyldimethylsily0oxy)-1-(5-(trifluoromethyppyrimidin-2-yOpiperidin-4-y1)-2-
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oxopyrrolidin-3-yl)oxy)propan-2-yl)carbamate as a yellow solid. LCMS (ESI,
m/z): 618.35
[M+H]+.
Step F
A solution of tert-butyl ((S)-1-4(R)-1-43S,4R)-3-((tert-butyldimethylsily0oxy)-
1-(5-
(trifluoromethyppyrimidin-2-yOpiperidin-4-y1)-2-oxopyrrolidin-3-y0oxy)propan-2-
yOcarbamate (790 mg, 1.28 mmol, 1.0 equiv) in 4M HC1 in dioxane (10 mL) was
stirred for 1
hour at room temperature. The mixture was concentrated in vacuo to afford 600
mg (96%
yield) of (R)-3-((S)-2-aminopropoxy)-1-((3S,4R)-3-hydroxy-1-(5-
(trifluoromethyl)pyrimidin-
2-yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride as a white solid. (ESI,
m/z): 461.25
[M+H]+.
Step G
To a solution of (R)-3-((S)-2-aminopropoxy)-1-((3S,4R)-3-hydroxy-1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride
(650 mg, 1.6
mmol, 1.0 equiv) in ethanol (8 mL) was added 5-chloro-2-(4-methoxybenzy1)-4-
(trifluoromethyl)pyridazin-3(2H)-one (616 mg, 1.93 mmol, 1.2 equiv) and
triethylamine
(1.04 g mg, 8.06 mmol, 5.0 equiv). The resulting solution was stirred for 4
hours at 60 C and
then was concentrated in vacuo. The crude product was applied onto a silica
gel column
eluting with ethyl acetate/petroleum ether (10/1) to afford 550 mg (50% yield)
of 5-(((S)-1-
(((R)-1-((3S,4R)-3-hydroxy-1-(5-(trifluoromethyppyridin-2-yOpiperidin-4-y1)-2-
oxopyrrolidin-3-y0oxy)propan-2-y0amino)-2-(4-methoxybenzyl)-4-
(trifluoromethyppyridazin-3(2H)-one as a yellow solid. LCMS (ESI, m/z): 686.20
[M+Hr.
Step H
A solution of 5-(((S)-1-(((R)-1-((3S,4R)-3-hydroxy-1-(5-
(trifluoromethyppyridin-2-
yOpiperidin-4-y1)-2-oxopyrrolidin-3-y0oxy)propan-2-y0amino)-2-(4-
methoxybenzyl)-4-
(trifluoromethyl)pyridazin-3(2H)-one (550 mg, 0.80 mmol, 1.0 equiv) in
Tf0H/TFA (3 mL,
1:10) was stirred for 2 hours at room temperature and then quenched by the
addition of water
(5 mL). The pH was adjusted to 7-8 with sodium bicarbonate. The resulting
solution was
extracted with 3 x 20 mL of ethyl acetate. The organic layers were combined,
dried over
anhydrous sodium sulfate and concentrated. The crude product was purified by
reverse phase
chromatography eluting with water/CH3CN (3/2) to afford 189 mg (42% yield) of
5-(((S)-1-
(((R)-1-((3S,4R)-3-hydroxy-1-(5-(trifluoromethyppyrimidin-2-yOpiperidin-4-y1)-
2-
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oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-
one as an
off-white solid. LCMS (ESI, m/z): 566.25 [M+H1+; 11-1NMR (400 MHz, DMSO-d6) 6
12.47
(s, 1H), 8.65 (s, 2H), 7.96 (s, 1H), 6.38 (br, 1H), 5.06 (d, J= 5.1 Hz, 1H),
4.93 - 4.78(m, 2H),
4.21 - 4.09 (m, 2H), 4.02 - 3.94(m, 1H), 3.92¨ 3.81 (m, 2H), 3.62 - 3.56 (m,
2H), 3.26¨ 3.10
(m, 2H), 3.04 (t, J= 12.6 Hz, 1H), 2.29 ¨ 2.18 (m, 1H), 2.12¨ 1.99 (m, 1H),
1.83 ¨ 1.69 (m,
1H), 1.53 (d, J= 12.3 Hz, 1H), 1.18 (d, J= 6.4 Hz, 3H).
Example 60: Synthesis of 5-0(S)-1-0(R)-1-03R,4S)-3-hydroxy-1-(5-
(trifluoromethyppyrimidin-2-yl)piperidin-4-y1)-2-oxopyrrolidin-3-yl)oxy)propan-
2-
yl)amino)-4-(trifluoromethyppyridazin-3(2H)-one
Boc,NH NH2 HCI
Boc-NH ..HO
A B ___ N'C ..
HO.----) ._ N
w-
NH N ' N N N
y y
c3 CF3 Boc
HO NH
TBs, H2N C1r0
N
C-.0
0....a
D TBS00-a E -..T.0
F
N _____________________ . N
,1--- ),--N
N ' N TBSO
N
Nq . It
y
0F3 0F3 0F3
0 0
NH2 HCI F3C....õ...kN - PM B
F3C:OH
I '
..- N
0 HN--...."'* N HN
G ".L\--0 0 H ,s,,=...__(:)
0
....1N N
HO ....N.--iN--.)--CF3
...c\NCF3
N N
HO HO
N "."--CF3
Step A
To a solution of tert-butyl ((3R,4S)-3-hydroxypiperidin-4-yl)carbamate (1.02
g, 4.71
mmol, 1.0 equiv) in DMF (6 mL) was added K2CO3 (980 mg, 7.2 mmol, 1.5 equiv)
and 2-
chloro-5-(trifluoromethyl)pyrimidine (863 mg, 4.73 mmol, 1.0 equiv). The
resulting solution
was stirred for 2 hours at 60 C and was then quenched by the addition of
water (20 mL). The
solids were collected by filtration to afford 1.59 g (93% yield) of tert-butyl
((3R,4S)-3-
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hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)carbamate as an
off-white solid.
LCMS (ESI, m/z): 363.10 [M+Hr.
Step B
To a solution of tert-butyl ((3R,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-
2-
yl)piperidin-4-yl)carbamate (1.59 g, 4.39 mmol, 1.0 equiv) in dioxane (50 mL)
was added 4N
HC1 in dioxane (30 mL). The resulting solution was stirred for 5 hours and was
then
concentrated to afford 1.43 g (97% yield) of (3R,4S)-4-amino-1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-3-ol hydrochloride as a yellow solid
that was taken
on without further purification. LCMS (ESI, m/z): 263.10 [M+H1+.
Step C
To a solution of (3R,4S)-4-amino-1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-3-ol
hydrochloride (1.43 g, 4.26 mmol, 1.0 equiv) in CH3CN (30 mL) was added
imidazole (2.20
g, 32.3 mmol, 7.6 equiv) and tert-butylchlorodimethylsilane (4.05 g, 26.9
mmol, 6.3 equiv).
The resulting solution was stirred for 15 hours at 60 C and then was
concentrated in vacuo.
The crude product was applied onto a silica gel column eluting with
dichloromethane/methanol (19/1) to afford 1.74 g (98% yield) of (3R,4S)-3-
((tert-
butyldimethylsily0oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-amine
as an orange
oil. LCMS (ESI, m/z): 377.20 [M+H1+.
Step D
To a solution of (3R,4S)-3-((tert-butyldimethylsilypoxy)-1-(5-
(trifluoromethyppyrimidin-2-yOpiperidin-4-amine (1.74 g, 4.16 mmol, 1.0 equiv)
in DCM
(50 mL) was added (R)-2-(2,2-dimethy1-5-oxo-1,3-dioxolan-4-yOacetaldehyde
(3.71 g, 23.5
mmol, 5.6 equiv) and AcOH (0.57 g, 9.6 mmol, 2.3 equiv). The resulting
solution was stirred
for 1 hour, and then STAB (3.04 g, 14.3 mmol, 3.5 equiv) was added, and the
mixture was
stirred an additional 3 hours. The reaction was quenched by the addition of 50
mL of
saturated aqueous sodium bicarbonate. The resulting solution was extracted
with 3 x 60 mL
of DCM. The organic layers were combined, dried over anhydrous sodium sulfate,
filtered
and concentrated in vacuo. The crude product was applied onto a silica gel
column eluting
with ethyl acetate/petroleum ether (2/1) to afford 1.16 g (56% yield) of (R)-1-
((3R,45)-3-
((tert-butyldimethylsily0oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-
y1)-3-
hydroxypyrrolidin-2-one as an off-white solid. LCMS (ESI, m/z): 461.20 [M+H1+.
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Step E
To a solution of (R)-1-((3R,4S)-3-((tert-butyldimethylsily0oxy)-1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-y1)-3-hydroxypyrrolidin-2-one
(1.12 g, 2.43
mmol, 1.0 equiv) in DMF (10 mL) was added NaH (437 mg, 11.0 mmol, 4.5 equiv,
60%
dispersion in mineral oil) at 0 C. The resulting solution was stirred for 30
min, and then a
solution of tert-butyl (S)-4-methy1-1,2,3-oxathiazolidine-3-carboxylate 2,2-
dioxide (700 mg,
3 mmol, 1.2 equiv) in DMF (2 mL) was added. The reaction mixture stirred for
13 hours and
then was quenched by the addition of ice water (10 mL). The pH was adjusted to
¨6-7 with
2N HC1. The resulting solution was extracted with 3 x 60 mL of ethyl acetate.
The organic
layers were combined, dried over anhydrous sodium sulfate and concentrated in
vacuo. The
crude product was applied onto a silica gel column eluting with ethyl
acetate/petroleum ether
(1/2) to afford 790 mg (52% yield) of tert-butyl ((S)-1-4(R)-1-43R,4S)-3-
((tert-
butyldimethylsily0oxy)-1-(5-(trifluoromethyppyrimidin-2-yOpiperidin-4-y1)-2-
oxopyrrolidin-3-y0oxy)propan-2-yOcarbamate as a light yellow solid. LCMS (ESI,
m/z):
618.35 [M+1-11+.
Step F
A solution of tert-butyl ((S)-1-4(R)-1-43R,4S)-3-((tert-butyldimethylsily0oxy)-
1-(5-
(trifluoromethyppyrimidin-2-yOpiperidin-4-y1)-2-oxopyrrolidin-3-y0oxy)propan-2-
yOcarbamate (790 mg, 1.28 mmol, 1.0 equiv) in 4N HC1 in dioxane (20 mL) was
stirred for
1.5 days at room temperature. The resulting mixture was concentrated in vacuo
to afford 600
mg of (R)-3-((S)-2-aminopropoxy)-1-((3R,4S)-3-hydroxy-1-(5-
(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride as a yellow solid that was
carried on without
further purification. LCMS (ESI, m/z): 404.20 [M+1-11+.
Step G
To a solution of (R)-3-((S)-2-aminopropoxy)-1-((3R,4S)-3-hydroxy-1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride
(593 mg, 1.35
mmol, 1.0 equiv) in CH3CN (15 mL) was added diisopropylethylamine (750 mg, 5.8
mmol,
4.3 equiv) and 5-chloro-2-(4-methoxybenzy1)-4-(trifluoromethyl)pyridazin-
3(211)-one (452
mg, 1.42 mmol, 1.1 equiv). The resulting solution was stirred for 7 hours at
60 C and then
was quenched by the addition of water (20 mL). The resulting solution was
extracted with 2 x
30 mL of ethyl acetate. The organic layers were combined, dried over anhydrous
sodium
sulfate and concentrated in vacuo. The crude product was applied onto a
reverse phase
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column eluting with water/CH3CN (1/3) to afford 706 mg (64% yield) of 5-(((S)-
1-(((R)-1-
((3R,4S)-3-hydroxy-1-(5-(trifluoromethyppyrimidin-2-yOpiperidin-4-y1)-2-
oxopyrrolidin-3-
y0oxy)propan-2-y0amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-
3(211)-one as
an off-white solid. LCMS (ESI, m/z): 686.10 [M+Hr.
Step H
A solution of 5-(((S)-1-(((R)-1-((3R,4S)-3-hydroxy-1-(5-
(trifluoromethyppyrimidin-
2-yOpiperidin-4-y1)-2-oxopyrrolidin-3-y0oxy)propan-2-y0amino)-2-(4-
methoxybenzyl)-4-
(trifluoromethyl)pyridazin-3(2H)-one (706 mg, 1.03 mmol, 1.0 equiv) in
TFA/TfOH (4.5 mL,
10:1) was stirred for 1 hour at 0 C and then was quenched by the addition of
ice water (10
mL). The pH was adjusted to 7 with saturated aqueous NaHCO3. The resulting
solution was
extracted with 3 x 30 mL of DCM. The organic layers were combined, dried over
anhydrous
sodium sulfate and concentrated in vacuo. The residue was purified by reverse
phase
chromatography eluting with water/CH3CN (2/1) to afford 254 mg (43% yield) of
5-(((S)-1-
(((R)-1-((3R,4S)-3-hydroxy-1-(5-(trifluoromethyppyrimidin-2-yOpiperidin-4-y1)-
2-
oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-
one as a light
green solid. LCMS (ESI, m/z): 566.15 [M+H1+; 1FINMR (400 MHz, DMSO-d6) 6 12.45
(s,
1H), 8.65 (s, 2H), 7.95 (s, 1H), 6.39 ¨ 6.27 (m, 1H), 5.02 (d, J= 5.1 Hz, 1H),
4.89 ¨ 4.75 (m,
2H), 4.22 ¨ 4.15 (m, 1H), 4.11 (t, J= 7.6 Hz, 1H), 4.08 ¨ 3.96 (m, 1H), 3.91
(br, 1H), 3.83
(dd, J = 10.0, 6.5 Hz, 1H), 3.61 (dd, J = 10.0, 4.7 Hz, 1H), 3.44¨ 3.36 (m,
1H), 3.35 ¨ 3.26
(m, 1H), 3.13 (d, J= 13.5 Hz, 1H), 3.09 ¨ 2.99 (m, 1H), 2.30 ¨ 2.18 (m, 1H),
2.12¨ 1.99 (m,
1H), 1.77¨ 1.65 (m, 1H), 1.52¨ 1.42 (m, 1H), 1.18 (d, J= 6.5 Hz, 3H).
Example 61: Synthesis (S)-N-OR)-2-oxo-1-(1-(5-(trifluoromethyppyrimidin-2-
yl)piperidin-4-yl)pyrrolidin-3-y1)-2-06-oxo-5-(trifluoromethyl)-1,6-
dihydropyridazin-4-
yl)amino)propanamide.
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o
A = N
____________________________ .==
)fj
HCI Boc N
N Boc NcF3 +S ur3
CF3 I I-
BOC-NH H2N
0
HCI
N
CF3 CF3
0
0
F3CAN-PMB F3CJLNH
I
HN
" N 0
0N/N
CF3
CF3
Step A
To a solution of (2R)-2-1(tert-butoxycarbonyl)amino1-4-
(methylsulfanyl)butanoic acid
(2.65 g, 10.6 mmol, 1.0 equiv) in DMF (20 mL) was added 1-15-
(trifluoromethyppyrimidin-
2-yllpiperidin-4-amine hydrochloride (3.00 g, 10.6 mmol, 1.00 equiv), HATU
(4.44 g, 11.7
mmol, 1.1 equiv) and diisopropylethylamine (4.11 g, 31.8 mmol, 3.0 equiv). The
resulting
solution was stirred for 1 hour and then was quenched by the addition of water
(20 mL) and
was extracted with 3 x 20 mL of ethyl acetate. The organic layers combined,
dried over
anhydrous sodium sulfate and concentrated in vacuo. The residue was applied
onto a silica
gel column with ethyl acetate/petroleum ether (1/1) to afford 3.9 g (77%
yield) of tert-butyl
(R)-(4-(methylthio)-1-oxo-1-((1-(5-(trifluoromethyppyrimidin-2-yOpiperidin-4-
y0amino)butan-2-yOcarbamate as a yellow oil. LCMS (ESI, m/z): 478.20 [M+1-11+.
Step B
To a solution of tert-butyl (R)-(4-(methylthio)-1-oxo-1-((1-(5-
(trifluoromethyppyrimidin-2-yOpiperidin-4-y0amino)butan-2-yOcarbamate (3.87 g,
8.10
mmol, 1.0 equiv) in DMF (50 mL) was added methyl iodide (1.73 g, 12.2 mmol,
1.5 equiv).
The resulting solution was stirred overnight at 30 C and then was
concentrated in vacuo to
afford 4.7 g (94% yield) of (R)-(3-((tert-butoxycarbonyl)amino)-4-oxo-4-41-(5-
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(trifluoromethyppyrimidin-2-yOpiperidin-4-y0amino)butyl)dimethylsulfonium
iodide as a
yellow oil. LCMS (ESI, m/z): 492.23 [Mr.
Step C
To a solution of (R)-(3-((tert-butoxycarbonyl)amino)-4-oxo-4-41-(5-
(trifluoromethyppyrimidin-2-yOpiperidin-4-y0amino)butyl)dimethylsulfonium
iodide (4.7 g,
7.6 mmol, 1.0 equiv) in DMF (100 mL) was added sodium hydride (970 mg, 40.4
mmol, 5.3
equiv, 60% dispersion in mineral oil). The resulting solution was stirred
overnight at 30 C
and then was quenched by the addition of 100 mL of water and was extracted
with 3 x 100
mL of DCM. The organic layers were combined, washed with water, dried and
concentrated
in vacuo. The crude product was recrystallized from PE:Et0Ac(10:1) to afford 2
g (61%
yield) of tert-butyl (R)-(2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-
yl)pyrrolidin-3-yl)carbamate as a white solid. LCMS (ESI, m/z): 430.20 [M+1-
11+.
Step D
A solution of tert-butyl (R)-(2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-
__ 4-yl)pyrrolidin-3-yl)carbamate (2.00 g, 4.66 mmol, 1.00 equiv) in 4N HC1 in
dioxane (10
mL) was stirred for 2 hours and then was concentrated in vacuo to afford 1.5 g
(98% yield) of
(R)-3-amino-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-
2-one
hydrochloride as a light yellow solid. LCMS (ESI, m/z): 330.15 [M+1-11+.
Step E
To a solution of (1-(4-methoxybenzy1)-6-oxo-5-(trifluoromethyl)-1,6-
dihydropyridazin-4-y1)-L-alanine (1.4 g, 8 equiv) in DMF (20 mL) was added (R)-
3-amino-1-
(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one
hydrochloride (155 mg,
1.0 equiv), HATU (179 mg, 1 equiv) and diisopropylethylamine (243 mg). After 2
hours, the
reaction was quenched by the addition of 100 mL of water and was extracted
with 3 x 100
mL of ethyl acetate. The organic layers were combined, dried over anhydrous
sodium sulfate
and concentrated in vacuo. The crude product was purified by reverse phase
chromatography
eluting with water/CH3CN (2/3) to afford 220 mg (66% yield) of (S)-2-41-(4-
methoxybenzy1)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-y1)amino)-N-
((R)-2-oxo-
1-(1-(5-(trifluoromethyppyrimidin-2-yOpiperidin-4-yOpyrrolidin-3-y0propanamide
as a
white solid. LC-MS (ESI, m/z): 683.25 [M+Hr.
Step F
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To a solution of (S)-2-((1-(4-methoxybenzy1)-6-oxo-5-(trifluoromethyl)-1,6-
dihydropyridazin-4-y1)amino)-N-((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-
y1)piperidin-4-y1)pyrrolidin-3-y1)propanamide (210 mg, 0.31 mmol, 1.0 equiv)
in TFA (2.7
mL) was added TfOH (0.3 mL). The mixture was stirred for 2 hours, and then 50
mL of
water was added. The pH was adjusted to 7 with saturated aqueous Na2CO3. The
resulting
solution was extracted with 3 x 100 mL of ethyl acetate. The organic layers
were combined,
dried over anhydrous sodium sulfate and concentrated in vacuo. The crude
product was
purified by reverse phase chromatography eluting with water/CH3CN (1/1) to
afford 81 mg
(46% yield) of (S)-N-((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-
yOpyrrolidin-3-y1)-2-46-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-
y0amino)propanamide as a white solid. LCMS (ESI, m/z): 563.10 [M+Hr. 1H NMR
(300
MHz, DMSO-d6) 6 12.61 (s, 1H), 8.70 (s, 2H), 8.59 (d, J= 8.0 Hz, 1H), 7.65 (s,
1H), 6.71
(br, 1H), 4.93 ¨ 4.69 (m, 2H), 4.53 ¨ 4.31 (m, 2H), 4.09 (br, 1H), 3.30 ¨ 3.24
(m, 1H), 3.24 ¨
3.11 (m, 1H), 3.11 ¨2.94 (m, 2H), 2.36 ¨ 2.18 (m, 1H), 1.82¨ 1.47 (m, 5H),
1.37 (d, J= 6.7
__ Hz, 3H).
Example 62: Synthesis of 5-0(S)-1-0(R)-2-oxo-1-(1-(5-(trifluoromethyppyrimidin-
2-
yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)-3-((2,2,2-trifluoroethyl)amino)propan-2-
yl)amino)-4-(trifluoromethyppyridazin-3(2H)-one.
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..õ....,-.... ...._õõcF3 CF3
N 1
N N I\JI
I CF3
0
(
NOal A 0 M\11 N
> Boc B 0
.-
HCI ......1.1,7
Oi."11 H2Nõ0
HO-
0 0
F3Cj-L ,PMB F3CAN,PMB
I Y D 1 C HNN 0 HN li 0
N- _-- N-__---
H0õ.Ø... CF3 Ts0õ..0 CF3
0
F3CJ.LY ,PMB 0
E I F3CJLN,PMB
HNN 0 F I I
N3õ,=0 CF3 HN 0
H2Nõ,=0Ni.___CN___4N-McF3
N
0 0
G
F3Cj-LNPMB
F3Cj-LI NI H
1 HN NI H HNN 0
0
N¨CCF3
N-_--- F3C
F3CHµ,.Ø... N4N-1-CF3
Step A
To a solution of (R)-3-hydroxy-1-(1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-
yl)pyrrolidin-2-one (1.30 g, 3.94 mmol, 1.0 equiv) in DMF (40 mL) was added
NaH (0.47 g,
11.8 mmol, 3 equiv, 60% dispersion in mineral oil) and tert-butyl (S)-2,2-
dimethy1-4-
((tosyloxy)methyl)oxazolidine-3-carboxylate (6.07 g, 15.7 mmol, 4 equiv). The
mixture was
stirred for 7 hours at 40 C. The reaction was quenched by addition of 40 mL
of water. After
extraction with ethyl acetate, drying organics over sodium sulfate, and
filtering, the resulting
mixture was concentrated and applied onto a silica gel column eluting with
ethyl
acetate/petroleum ether (34/66) to afford tert-butyl (R)-2,2-dimethy1-4-4((R)-
2-oxo-1-(1-(5-
(trifluoromethyppyrimidin-2-yOpiperidin-4-yOpyrrolidin-3-
y0oxy)methypoxazolidine-3-
carboxylate (1.12 g, 47% yield) as a white solid. LCMS (ESI, m/z): 544.30 [M+1-
11+.
Step B
A solution of tert-butyl (R)-2,2-dimethy1-4-((((R)-2-oxo-1-(1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-
yl)oxy)methyl)oxazolidine-3-
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carboxylate (1.12 g, 2.06 mmol, 1.0 equiv) in 1,4-dioxane (10 mL) was treated
with 4N HC1
in dioxane (5 mL). The resulting solution stirred for 3 hours and was
concentrated to afford
(R)-3-((S)-2-amino-3-hydroxypropoxy)-1-(1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-
yl)pyrrolidin-2-one hydrochloride (600 mg, 65% yield) as a yellow oil. LCMS
(ESI, m/z):
.. 404.20 [M+H]+.
Step C
To a solution of (R)-3-((S)-2-amino-3-hydroxypropoxy)-1-(1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride
(420 mg, 0.96
mmol, 1.0 equiv) in i-PrOH (45 mL) was added 5-chloro-2-(4-methoxybenzy1)-4-
(trifluoromethyl)pyridazin-3(2H)-one (304 mg, 0.96 mmol, 1 equiv) and
diisopropyl
ethylamine (987 mg, 7.64 mmol, 8 equiv). The resulting solution was stirred
for 3 hours at 80
C and then was diluted with 150 mL of ethyl acetate. The mixture was washed
with 3 x 50
mL of water and then was dried over anhydrous sodium sulfate and concentrated
in vacuo.
The residue was applied onto a silica gel column eluting with ethyl acetate to
afford 5-(((S)-
.. 1-hydroxy-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyppyrimidin-2-yOpiperidin-4-
yOpyrrolidin-3-
y0oxy)propan-2-y0amino)-2-(4-methoxybenzyl)-4-(trifluoromethyppyridazin-3(2H)-
one
(440 mg, 60% yield) as a yellow oil. LCMS (ESI, m/z): 686.25 [M+F11+.
Step D
To a solution of 5-(((S)-1-hydroxy-3-(((R)-2-oxo-1-(1-(5-
(trifluoromethyppyrimidin-
2-yOpiperidin-4-yOpyrrolidin-3-y0oxy)propan-2-y0amino)-2-(4-methoxybenzyl)-4-
(trifluoromethyppyridazin-3(2H)-one (775 mg, 1.13 mmol, 1.0 equiv) in DCM (30
mL) was
added DMAP (27 mg, 0.23 mmol, 0.2 equiv), triethylamine (343 mg, 3.39 mmol,
3.0 equiv)
and 4-methylbenzenesulfonyl chloride (430 mg, 2.3 mmol, 2 equiv). The
resulting solution
was stirred overnight and then was concentrated and applied onto a silica gel
column eluting
with ethyl acetate/petroleum ether (71/29) to afford (R)-2-41-(4-
methoxybenzy1)-6-oxo-5-
(trifluoromethyl)-1,6-dihydropyridazin-4-y1)amino)-3-(((R)-2-oxo-1-(1-(5-
(trifluoromethyl)pyrimidin-2-y1)piperidin-4-y1)pyrrolidin-3-y1)oxy)propyl 4-
methylbenzenesulfonate (330 mg, 30% yield) as a yellow oil. LCMS (ESI, m/z):
840.25
[M+H]+.
Step E
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To a solution of (R)-2-((1-(4-methoxybenzy1)-6-oxo-5-(trifluoromethyl)-1,6-
dihydropyridazin-4-y0amino)-3-4(R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-y1)pyrrolidin-3-y1)oxy)propyl 4-methylbenzenesulfonate (330 mg,
0.39 mmol,
1.0 equiv) in DMF (5 mL) was added sodium azide (38 mg, 0.59 mmol, 1.5 equiv).
The
solution was stirred for 1 hour at 80 C and then was quenched by the addition
of 25 mL of
water. The mixture was extracted with 3 x 50 mL of ethyl acetate. The combined
organics
were dried over anhydrous sodium sulfate and concentrated to afford 5-(((2S)-1-
azido-3-((2-
oxo-1-(1-(5 -(trifluoromethy Opy rimi din-2-y Opi pen din-4-y Opyrroli din-3 -
y Doxy)prop an-2-
yOamino)-2-(4-methoxybenzy1)-4-(trifluoromethyppyridazin-3(2H)-one (330 mg,
71% yield)
as a yellow oil. LCMS (ESI, m/z): 711.20 [M+Hr.
Step F
To a solution of 5-(((2S)-1-azido-3-((2-oxo-1-(1-(5-(trifluoromethyppyrimidin-
2-
yOpiperidin-4-yOpyrrolidin-3-y0oxy)propan-2-y0amino)-2-(4-methoxybenzyl)-4-
(trifluoromethyl)pyridazin-3(2H)-one (330 mg, 0.46 mmol, 1.0 equiv, 60%) in
THF (5 mL)
was added triphenylphosphine (182 mg, 0.70 mmol, 1.5 equiv) and water (0.5
mL). The
solution was stirred 1.5 hours at 60 C, concentrated, and applied onto a
silica gel column
eluting with DCM/methanol (87/13) to afford 5-(((2S)-1-amino-3-((2-oxo-1-(1-(5-
(trifluoromethyppyrimidin-2-yOpiperidin-4-yOpyrrolidin-3-y0oxy)propan-2-
y0amino)-2-(4-
methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (186 mg, 92% yield) as a
white
solid. LCMS (ESI, m/z): 685.30 [M+Hr.
Step G
To a solution of 5-(((2S)-1-amino-3-((2-oxo-1-(1-(5-(trifluoromethyppyrimidin-
2-
yOpiperidin-4-yOpyrrolidin-3-y0oxy)propan-2-y0amino)-2-(4-methoxybenzyl)-4-
(trifluoromethyl)pyridazin-3(2H)-one (100 mg, 0.15 mmol, 1.00 equiv) in
dichloroethane (8
mL) was added 2,2,2-trifluoroacetaldehyde (57 mg, 0.44 mmol, 3 equiv), Ti(Oi-
Pr)4 (41 mg,
0.15 mmol, 1.0 equiv), AcOH (8 mg, 0.15 mmol, 1 equiv), and NaBH3CN (18 mg,
0.29
mmol, 2 equiv). The resulting solution was stirred for 1.5 hours at 70 C and
then was diluted
with 50 mL of ethyl acetate and was washed with 3 x 20 ml of water. The
organic layers were
combined, dried over anhydrous sodium sulfate and concentrated. The residue
was applied
.. onto a silica gel column eluting with ethyl acetate/petroleum ether (91/9)
to afford 2-(4-
methoxy benzy1)-5 -(((S )-1 -(((R)-2-oxo-1 -(1-(5-(trifluoromethyl)py rimi din-
2-yl)piperi din-4-
yl)pyrrolidin-3-yl)oxy)-3-((2,2,2-trifluoroethyl)amino)propan-2-yl)amino)-4-
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(trifluoromethyl)pyridazin-3(2H)-one (67 mg, 56% yield) as a white solid. LCMS
(ESI, m/z):
767.25 [M+H1+.
Step H
To a solution of 2-(4-methoxybenzy1)-5-4(S)-1-4(R)-2-oxo-1-(1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)-3-((2,2,2-
trifluoroethyl)amino)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
(60 mg,
0.08 mmol, 1.0 equiv) in TFA (1 mL) was added TfOH (0.1 mL), and the mixture
was stirred
for 1 hour. 8 mL of water was added, and the pH was adjusted to 9 with solid
Na2CO3. The
resulting solution was extracted with 2 x 30 mL of ethyl acetate. The organic
layers were
combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The
residue was
applied onto a reverse phase column eluting with water/CH3CN (37/63) to afford
5-(((S)-1-
(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-
3-yl)oxy)-3-
((2,2,2-trifluoroethyl)amino)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-
3(2H)-one (20
mg, 39% yield) as a white solid. LCMS (ESI, m/z): 647.20 [M+H1+; 11-1 NMR(300
MHz,
DMSO-d6) 6 12.45 (s, 1H), 8.69 (s, 2H), 7.96 (s, 1H), 6.60¨ 6.60 (m, 1H), 4.82
(d, J= 13.2
Hz, 2H), 4.20 ¨ 4.01 (m, 4H), 3.95 ¨3.82 (m, 1H), 3.72¨ 3.58 (m, 1H), 3.18
¨2.96 (m, 4H),
2.92 ¨2.89 (m, 1H), 2.85 ¨2.78 (m, 1H), 2.30 ¨ 2.15 (m, 1H), 1.81 ¨ 1.50 (m,
6H).
Example 63: Synthesis of 5-4(S)-1-hydroxy-3-4(R)-2-oxo-1-(1-(5-
(trifluoromethyppyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)propan-2-
yl)amino)-
4-(trifluoromethyl)pyridazin-3(2H)-one.
0
HO NH2 HCI 0 A F3C I N_PMB
I
0 N
HN 0CF
t-N---C\ HO .= 0
3
N t.A-3
0
F3CI NI H
HNN 0
CF3
Step A
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To a solution of (R)-3-((S)-2-amino-3-hydroxypropoxy)-1-(1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one hydrochloride
(130 mg, 0.29
mmol, 1.0 equiv) in CH3CN (5 mL) was added 5-chloro-2-(4-methoxybenzy1)-4-
(trifluoromethyppyridazin-3(2H)-one (106 mg, 0.33 mmol, 1.1 equiv) and
triethylamine (101
mg, 1.00 mmol, 3.4 equiv). The resulting solution was stirred for 1.5 days at
60 C and then
was concentrated in vacuo. The crude product was applied onto a reverse phase
column
eluting with water/CH3CN (1/1) to afford 150 mg (62% yield) of 5-(((S)-1-
hydroxy-3-4(R)-
2-oxo-1-(1-(5-(trifluoromethyppyrimidin-2-yOpiperidin-4-yOpyrrolidin-3-
y0oxy)propan-2-
y0amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one as a
yellow solid.
LCMS (ES, m/z): 686.20 [M+H1+.
Step B
A solution of 5-(((5)-1-hydroxy-3-(((R)-2-oxo-1-(1-(5-
(trifluoromethyppyrimidin-2-
yOpiperidin-4-yOpyrrolidin-3-y0oxy)propan-2-y0amino)-2-(4-methoxybenzyl)-4-
(trifluoromethyl)pyridazin-3(211)-one (150 mg, 0.22 mmol, 1.0 equiv) in
TFA/TfOH (1.5 mL,
10:1) was stirred for 1 hour at room temperature, and then was quenched by the
addition of
ice water (10 mL). The pH was neutralized with saturated aqueous NaHCO3, and
the
resulting solution was extracted with 3 x 30 mL of DCM. The organic layers
were combined,
dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was
purified by
reverse phase chromatography eluting with water/CH3CN (3/2) to afford 15 mg
(12% yield)
of 5-(((S)-1-hydroxy-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-
yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(211)-
one as an off-
white solid. LCMS (ESI, m/z): 566.25 [M+H1+; 11-1 NMR (400 MHz, DMSO-d6) 6
12.45 (br,
1H), 8.69 (s, 1H), 7.95 (s, 1H), 6.29 - 6.31 (m, 1H), 5.10 (t, J= 5.2 Hz, 1H),
4.82 (d, J = 12.8
Hz, 1H), 4.13 -4.07 (m, 3H), 3.88 (dd, J= 10.1, 6.4 Hz, 1H), 3.68 (dd, J =
10.2, 5.4 Hz, 1H),
.. 3.54 (t, J= 5.4 Hz, 2H), 3.28 - 3.22 (m, 1H), 3.16 - 3.10 (m, 1H), 3.04 (t,
J= 11.6 Hz, 2H),
2.29 -2.21 (m, 1H), 1.77 - 1.50 (m, 5H).
Example 64: Synthesis of Syn-5-(42S)-1-(43S)-1-(3-hydroxy-1-(5-
(trifluoromethyl)pyrimidin-2-y1)piperidin-4-y1)-2-oxopyrrolidin-3-ypoxy)propan-
2-
ypoxy)-4-(trifluoromethyl)pyridazin-3(2H)-one and Syn-5-(((2S)-1-(((3R)-1-(3-
hydroxy-
1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-y1)-2-oxopyrrolidin-3-
yl)oxy)propan-2-
yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one.
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HN H2N
Boc
HNI HCI IBS\ _L
HO-
\)O-L)
0
A N\ N
HO-0 B 4-N
n N N\4
N \,_
CF3 CF3
CF3
HO, 0 Ts0,0
(NyN.1
C D r,._.
E
IV
TB ..-
N,... TB 9 N, a
S S II
N ,--
CF3 CF3
OH 0
THP\ iõ,.( F3CAN-PMB
0 \----0 I '
_,...0 ON
0 0
F ._--1V G ""..--0 0
TBS ---fN----IN....zN..,
.. N--/-
0 II , TBS NCF3 TBS-0
N--jCF3
0 0
F3Cj=L1 NH F3CJ.LNH
I '
ON 0.*N
H "".c.-0,e µ,".._.0 0
N
-----QN--iN) CF3 ----QN¨iN---)
CF3
N--7-- N---/-
HO HO
64A 64B
Step A
To a solution of racemic syn-tert-butyl (3-hydroxy-1-(5-
(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-yl)carbamate (2.22 g, 6.13 mmol, 1.0 equiv) in dioxane (10 mL)
was added 4N
HC1 in dioxane (10 mL, 4M). The solution was stirred for 1.5 hours at 50 C
and then was
concentrated in vacuo to afford 2.28 g (99% yield) of syn-4-amino-1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-3-ol hydrochloride as an off-white
solid. LCMS
(ESI, m/z): 263.05 [M+Hr.
Step B
To a solution of syn-4-amino-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-3-
ol
hydrochloride (2.28 g, 7.63 mmol, 1.0 equiv) in CH3CN (20 mL) was added
imidazole (3.15
g, 46.3 mmol, 6.1 equiv) and tert-butylchlorodimethylsilane (5.80 g, 38.5
mmol, 5.0 equiv).
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The solution was stirred for 15 hours at 60 C and then was concentrated in
vacuo. The crude
product was applied onto a silica gel column eluting with DCM/methanol (24/1)
to afford
2.27 g (78% yield) of syn-3-((tert-butyldimethylsily0oxy)-1-(5-
(trifluoromethyppyrimidin-2-
yOpiperidin-4-amine as alight yellow solid. LCMS (ESI, m/z): 377.10 [M+Hr.
Step C
To a solution of syn-3-((tert-butyldimethylsily0oxy)-1-(5-
(trifluoromethyl)pyrimidin-
2-yl)piperidin-4-amine (2.27 g, 6.03 mmol, 1.0 equiv) in DCM (50 mL) was added
(R)-2-
(2,2-dimethy1-5-oxo-1,3-dioxolan-4-yOacetaldehyde (5.70 g, 36.0 mmol, 5.98
equiv) and
AcOH (1.08 g, 17.9 mmol, 3.0 equiv). The resulting solution was stirred for 1
hour, and then
STAB (3.84 g, 18.1 mmol, 3.0 equiv) was added, and the mixture was stirred for
an
additional 3 hours. After completion, the reaction was quenched by the
addition of 50 mL of
saturated aqueous sodium bicarbonate and extracted with 3 x 60 mL of DCM. The
organic
layers were combined, dried over anhydrous sodium sulfate and concentrated in
vacuo. The
crude product was applied onto a silica gel column eluting with DCM/methanol
(24/1) to
afford 2.55 g (81% yield) of syn-(3S)-1-(3-((tert-butyldimethylsily0oxy)-1-(5-
(trifluoromethyppyrimidin-2-yOpiperidin-4-y1)-3-hydroxypyrrolidin-2-one as an
off-white
solid. LCMS (ESI, m/z): 461.15 [M+1-11+.
Step D
To a solution of syn-(35)-1-(3-((tert-butyldimethylsilypoxy)-1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-y1)-3-hydroxypyrrolidin-2-one
(2.40 g, 5.21
mmol, 1.0 equiv) in DCM (30 mL) was added triethylamine (2.19 g, 21.6 mmol,
4.2 equiv),
4-methylbenzenesulfonyl chloride (2.04 g, 10.7 mmol, 2.1 equiv) and DMAP (0.13
g, 1.07
mmol, 0.2 equiv). The resulting solution was stirred overnight at room
temperature, and then
was quenched by the addition of 50 mL of ice water. The solution was extracted
with 2 x 100
mL of DCM, dried over anhydrous sodium sulfate and concentrated in vacuo. The
crude
product was applied onto a silica gel column eluting with ethyl
acetate/petroleum ether (1:2
to 10:1) to afford 3.4 g (99% yield) of syn-(35)-1-(3-((tert-
butyldimethylsily0oxy)-1-(5-
(trifluoromethyppyrimidin-2-yOpiperidin-4-y1)-2-oxopyrrolidin-3-y1 4-
methylbenzenesulfonate as alight yellow solid. LCMS (ESI, m/z): 615.20 [M+Hr.
.. Step E
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To a solution of (2S)-2-((tetrahydro-2H-pyran-2-y0oxy)propan-1-ol (1.09 g,
6.80
mmol, 2.0 equiv) in DMF (20 mL) was added NaH (0.27 g, 6.85 mmol, 2.0 equiv,
60%
dispersion in mineral oil) at 0 C. The reaction mixture was stirred for 15
min, and then syn-
(3S)-1-(3-((tert-butyldimethylsily0oxy)-1-(5-(trifluoromethyppyrimidin-2-
yOpiperidin-4-y1)-
2-oxopyrrolidin-3-y1 4-methylbenzenesulfonate (2.10 g, 3.42 mmol, 1.0 equiv)
was added,
and the solution was stirred for 1 hour at room temperature. The reaction was
treated with
Me0H (5 mL), concentrated in vacuo and applied onto a silica gel column
eluting with ethyl
acetate/petroleum ether (1/2) to afford 775 mg (38% yield) of syn-1-(3-((tert-
butyldimethylsily0oxy)-1-(5-(trifluoromethyppyrimidin-2-yOpiperidin-4-y1)-3-
42S)-2-
((tetrahydro-2H-pyran-2-y0oxy)propoxy)pyrrolidin-2-oneas an off-white solid.
LCMS (ESI,
m/z): 603.20 [M+H]+.
Step F
To a solution of syn-1-(3-((tert-butyldimethylsily0oxy)-1-(5-
(trifluoromethyppyrimidin-2-yOpiperidin-4-y1)-3-42S)-2-((tetrahydro-2H-pyran-2-
yl)oxy)propoxy)pyrrolidin-2-one (500 mg, 0.8 mmol, 1 equiv) in Me0H (30 mL)
was added
pyridinium p-toluenesulfonate (210 mg, 0.83 mmol, 1.0 equiv). The resulting
solution was
stirred for 15 hours at room temperature and then was quenched by the addition
of solid
Na2CO3(200 mg). The resulting mixture was concentrated and applied onto a
silica gel
column eluting with ethyl acetate to afford 350 mg (79% yield) of 1-syn-3-
((tert-
butyldimethylsily0oxy)-1-(5-(trifluoromethyppyrimidin-2-yOpiperidin-4-y1)-3-
((S)-2-
hydroxypropoxy)pyrrolidin-2-one as a light yellow solid. LCMS (ESI, m/z):
519.20 [M+1-11+.
Step G
To a solution of syn-1-3-((tert-butyldimethylsilyl)oxy)-1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-y1)-3-((S)-2-
hydroxypropoxy)pyrrolidin-2-one
(360 mg, 0.70 mmol, 1.0 equiv) in DCM (5 mL) was added 5-chloro-2-[(4-
methoxyphenyOmethy11-4-(trifluoromethyl)pyridazin-3-one (301 mg, 0.95 mmol,
1.4 equiv)
and t-BuOK (290 mg, 2.6 mmol, 3.8 equiv) at 0 C. The resulting solution
stirred for 1.5
hours and then was concentrated and applied onto a silica gel column eluting
with ethyl
acetate/petroleum ether (1/1) to afford 471 mg (85% yield) of syn-5-(((2S)-1-
((1-3-((tert-
butyldimethylsily0oxy)-1-(5-(trifluoromethyppyrimidin-2-yOpiperidin-4-y1)-2-
oxopyrrolidin-3-y0oxy)propan-2-y0oxy)-2-(4-methoxybenzy1)-4-
(trifluoromethyl)pyridazin-
3(2H)-one as a white solid. LCMS (ESI, m/z): 801.3[M+Hr
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Step H
A solution of syn-5-(42S)-1-41-3-((tert-butyldimethylsily0oxy)-1-(5-
(trifluoromethyl)pyrimidin-2-yOpiperidin-4-y1)-2-oxopyrrolidin-3-y0oxy)propan-
2-y0oxy)-
2-(4-methoxybenzy1)-4-(trifluoromethyppyridazin-3(2H)-one (471 mg, 0.59 mmol,
1.0
equiv) in TFA/TfOH (3 mL, 10:1) was stirred for 2 hours at room temperature.
The reaction
was quenched by the addition of ice water (20 mL), and the pH was adjusted to
7 with
saturated aqueous Na2CO3. The solution was extracted with 3 x 60 mL of ethyl
acetate, and
the organic layers were combined, dried over anhydrous sodium sulfate and
concentrated in
vacuo. The residue was applied onto reverse phase chromatography eluting with
water/CH3CN (1/1) and was further purified by chiral prep HPLC with the
following
conditions: CHIRAL ART Cellulose-SB, 2*25 cm, 5 p.m; Mobile Phase A: Hex:DCM =
3:1
(10 mM NH3-Me0H); Mobile Phase B: IPA; Flow rate: 20 mL/min; Gradient: 30%B
for 7
min; 220/254 nm. The absolute stereochemistry of the pyrrolidone stereocenter
was assigned
by analogy to Example 10, based on the PARP7 potency of the more active
diastereomer and
in analogy to the Example 10B X-ray crystal structure. The absolute
stereochemistry of the
piperidine stereocenters was undetermined.
Example 64 Isomer A (64A): Syn-5-4(25)-1-4(35)-1-(3-hydroxy-1-(5-
(trifluoromethyppyrimidin-2-yOpiperidin-4-y1)-2-oxopyrrolidin-3-y0oxy)propan-2-
y0oxy)-
4-(trifluoromethyppyridazin-3(2H)-one (61 mg, 25% yield, off-white solid).
LCMS (ESI,
m/z): 567.20[M+Hr; NMR (400 MHz, DMSO-d6) 6 13.22 (s, 1H), 8.65 (s, 2H), 8.28
(s,
1H), 5.22 ¨ 5.15 (m, 1H), 5.00 (br, 1H), 4.90 ¨ 4.72 (m, 2H), 4.06¨ 3.95 (m,
3H), 3.90 (s,
1H), 3.63 (dd, J= 11.1, 8.0 Hz, 1H), 3.30¨ 3.24 (m, 2H), 3.14 ¨ 2.98 (m, 2H),
2.20 ¨ 2.16
(m, 1H), 2.07 ¨2.02 (m, 1H), 1.61 ¨ 1.58 (m, 1H), 1.49¨ 1.41 (m, 1H), 1.28 (d,
J= 6.2 Hz,
3H). Chiral HPLC: CHIRAL Cellulose-SB, 0.46*10 cm; 3 p.m; (Hex:DCM = 3:1 w/
0.1%
diethyl amine:IPA = 90:10; Flow rate:1 mL/min); Retention time: 3.726 min.
(faster peak).
Example 64 Isomer B (64B): Syn-5-4(25)-1-(43R)-1-(3-hydroxy-1-(5-
(trifluoromethyppyrimidin-2-yOpiperidin-4-y1)-2-oxopyrrolidin-3-y0oxy)propan-2-
y0oxy)-
4-(trifluoromethyppyridazin-3(2H)-one (144 mg, 59% yield, off-white solid).
LCMS (ESI,
m/z): 567.10[M+H1+1FINMR (400 MHz, DMSO-d6) 6 13.21 (s, 1H), 8.65 (s, 2H),
8.31 (s,
1H), 5.19 ¨ 5.15 (m, 1H), 5.00 (br, 1H), 4.88 ¨4.76 (m, 2H), 4.07 (t, J= 7.4
Hz, 1H), 4.04 ¨
3.98 (m, 1H), 3.93 ¨ 3.83 (m, 2H), 3.74 (dd, J = 11.1, 3.3 Hz, 1H), 3.30 ¨
3.24 (m, 2H), 3.17
¨2.98 (m, 2H), 2.28 ¨2.17 (m, 1H), 2.11 ¨ 1.97 (m, 1H), 1.71¨ 1.62(m, 1H),
1.47 (d, J=
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12.2 Hz, 1H), 1.28 (d, J= 6.2 Hz, 3H). Chiral HPLC: CHIRAL Cellulose-SB,
0.46*10 cm; 3
um; (Hex:DCM = 3:1 w/ 0.1% diethyl amine:IPA = 90:10; Flow rate:1 mL/min);
Retention
time: 5.703 min. (slower peak).
Example 65: Synthesis of 5-(((2S)-1-((1-((3R,4R)-3-hydroxy-1-(5-
(triflu oromethyppyrimid in-2-yl)piperidin-4-y1)-2-oxopyrrolidin-3-yl)oxy)p ro
p an-2-
yl)oxy)-4-(trifluoromethyl)pyrid azin-3(2H)-one
Boc
Boc HN H2N,. HCI
:
HN:
A H0.-0 B H0.-0
N C
'
HO.-0 .-- N
NH
N\ N\
CF3
CF3
Ts0, 0
HQ 0
H2N,.
TBS,0.0 F
D E
N . 0ON 0"-ON ..-N
)/--N .- ..-N
N\ TBS II
1\1:,õ--.iN TBS II
N ....:-...c
CF3
C
_______________ CF3 F3
THP\ OH 0
F3CAN,PMB
0 0
H s,0 N
_ 0
--t. , _________ 1 0 = 0 , ,
cN4N\I-MCF3
-'1 N
TBS.,0)*----, f\l G TBS0 NN-- "-e N
N------OF3
N)'--OF3 Os
TBS
0
J
F3C OH
0 N
I
..-
N--iNI-
N____, -CF3
HO
Step A
To a solution of tert-butyl((3R,4R)-3-hydroxypiperidin-4-yl)carbamate (2.00 g,
9.25
mmol, 1.00 equiv), 2-chloro-5-(trifluoromethyl)pyrimidine (1.69 g, 9.25 mmol,
1.00 equiv) in
DMF (20 mL) was added K2CO3 (2.56 g, 18.5 mmol, 2.00 equiv). The resulting
solution
stirred for 2 hours at 50 C and was quenched by the addition of 50 mL of ice
water. Then the
solids were collected by filtration to afford 2.8 g (84% yield) of tert-butyl
((3R,4R)-3-
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hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)carbamate as a
white solid.
LCMS (ESI, m/z): 363.10 [M+Hr.
Step B
A solution of tert-butyl ((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-yl)carbamate (2.80 g, 7.73 mmol, 1.00 equiv) in 4N HC1 in
dioxane (20 mL)
stirred for 1 hour. The mixture was concentrated to afford 2.6 g of crude
(3R,4R)-4-amino-1-
(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-3-ol as a clear oil that was
carried on without
further purification. LCMS (ESI, m/z): 263.05[M+H1t
Step C
To a solution of (3R,4R)-4-amino-1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-3-ol
(2.60 g, 9.92 mmol, 1.00 equiv) in CH3CN (15 mL) was added tert-
butyldimethylsilyl
chloride (5.98 g, 39.7 mmol, 4.00 equiv) and imidazole (5.40 g, 79.3 mmol,
8.00 equiv). The
resulting solution was stirred for 4 hours at 60 C and was then concentrated
in vacuo and
applied onto a silica gel column eluting with DCM/methanol (99/1) to afford
2.5 g (67%
yield) of (3R,4R)-3-(tert-butyldimethylsilyloxy)-1-(5-
(trifluoromethyppyrimidin-2-
yOpiperidin-4-amine as a yellow oil. LCMS (ESI, m/z): 377.15 [M+H1+.
Step D
To a solution of (3R,4R)-3-(tert-butyldimethylsilyloxy)-1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-amine (3.20 g, 8.50 mmol, 1.0
equiv) in DCM
and DMF (1:1, 90 mL) was added (S)-2-(2,2-dimethy1-5-oxo-1,3-dioxolan-4-
yOacetaldehyde
(2.69 g, 17.0 mmol, 2.0 equiv), STAB (7.21 g, 34.0 mmol, 4.0 equiv), and AcOH
(0.51 g, 8.5
mmol, 1.0 equiv). The solution was stirred for 6 hours and then quenched by
the addition of
90 mL of water. The solution was extracted with 3 x 180 mL of DCM, and the
combined
organics were concentrated in vacuo. The crude residue was applied onto a
silica gel column
with DCM/methanol (95/5) to afford 1.9 g (49% yield) of (S)-1-43R,4R)-3-(tert-
butyldimethylsilyloxy)-1-(5-(trifluoromethyppyrimidin-2-yOpiperidin-4-y1)-3-
hydroxypyrrolidin-2-one as a white solid. LCMS (ESI, m/z): 461.20 [M+1-11+.
Step E
To a solution of (S)-1-43R,4R)-3-(tert-butyldimethylsilyloxy)-1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-y1)-3-hydroxypyrrolidin-2-one
(1.00 g, 2.17
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mmol, 1.0 equiv) and TsC1 (496 mg, 2.61 mmol, 1.2 equiv) in DCM (10 mL) was
added
DMAP (265 mg, 2.17 mmol, 1.0 equiv) and triethylamine (439 mg, 4.34 mmol, 2.0
equiv).
The solution was stirred for 2 hours and then was saturated aqueous NaHCO3 was
added.
The layers were separated, and the aqueous layer was extracted with 3 x10 mL
of DCM. The
combined organic layers was washed with 3 x 30 mL of saturated aqueous NaHCO3,
dried
over anhydrous sodium sulfate, and concentrated in vacuo. The residue was
applied onto a
silica gel column eluting with ethyl acetate/petroleum ether (1/1) to afford
1.0 g (75% yield)
of (S)-1-43R,4R)-3-(tert-butyldimethylsilyloxy)-1-(5-(trifluoromethyppyrimidin-
2-
yOpiperidin-4-y1)-2-oxopyrrolidin-3-y14-methylbenzenesulfonate as a white
solid. LCMS
(ESI, m/z): 615.30 [M+Hr.
Step F
To a solution of (S)-1-43R,4R)-3-(tert-butyldimethylsilyloxy)-1-(5-
(trifluoromethyppyrimidin-2-yOpiperidin-4-y1)-2-oxopyrrolidin-3-y1 4-
methylbenzenesulfonate (540 mg, 0.88 mmol, 1.0 equiv) in DMF (5 mL) at 0 C
was added
NaH (42 mg, 1.8 mmol, 2.0 equiv, 60% dispersion in mineral oil), and the
mixture was stirred
for 15 min at 0 C. (2S)-2-(Oxan-2-yloxy)propan-1-ol (281 mg, 1.76 mmol, 2.0
equiv) was
added, and the mixture was stirred for an additional 30 min. The reaction was
then quenched
by the addition of 10 mL of Me0H, concentrated in vacuo, and applied onto a
silica gel
column eluting with ethyl acetate/petroleum ether (1/1) to afford 181 mg (34%
yield) of 1-
((3R,4R)-3-(tert-butyldimethylsilyloxy)-1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-y1)-
3-((S)-2-(tetrahydro-2H-pyran-2-yloxy)propoxy)pyrrolidin-2-one as a white
solid. LCMS
(ESI, m/z): 519.25 [M+1-11+.
Step G
To a solution of 1-((3R,4R)-3-(tert-butyldimethylsilyloxy)-1-(5-
.. (trifluoromethyppyrimidin-2-yOpiperidin-4-y1)-3-((S)-2-(tetrahydro-2H-pyran-
2-
yloxy)propoxy)pyrrolidin-2-one (180 mg, 0.30 mmol, 1.0 equiv) in Me0H (5 mL)
was added
pyridinium p-toluenesulfonate (75 mg, 0.30 mmol, 1.0 equiv). The resulting
solution was
stirred for 1 hour at 40 C and then was concentrated and applied onto a
silica gel column
eluting with ethyl acetate/petroleum ether (4/1) to afford 127mg (82% yield)
of 1-((3R,4R)-3-
.. (tert-butyldimethylsilyloxy)-1-(5-(trifluoromethyppyrimidin-2-yOpiperidin-4-
y1)-3-((S)-2-
hydroxypropoxy)pyrrolidin-2-one as white solid. LCMS (ESI, m/z): 519.20 [M+1-
11+.
Step H
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To a solution of 1-((3R,4R)-3-(tert-butyldimethylsilyloxy)-1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-y1)-3-((S)-2-
hydroxypropoxy)pyrrolidin-2-one
(120 mg, 0.2 mmol, 1 equiv) in DCM (5 mL) at 0 C was added t-BuOK (50 mg, 0.5
mmol, 2
equiv). The resulting solution was stirred for 15 min, and then 5-chloro-2-(4-
methoxybenzy1)-4-(trifluoromethyppyridazin-3(2H)-one (86 mg, 0.27 mmol, 1.2
equiv) was
added, and the mixture stirred for 1.5 hours at 0 C. The mixture was
concentrated, and the
residue was applied onto a silica gel column eluting with ethyl
acetate/petroleum ether (4/1)
to afford 62 mg (34% yield) of 5-((S)-1-(1-43R,4R)-3-(tert-
butyldimethylsilyloxy)-1-(5-
(trifluoromethyppyrimidin-2-yOpiperidin-4-y1)-2-oxopyrrolidin-3-yloxy)propan-2-
yloxy)-2-
.. (4-methoxybenzy1)-4-(trifluoromethyppyridazin-3(2H)-one as a white solid.
LCMS (ESI,
m/z): 801.35 [M+H]+.
Step I
A solution of 5-[[(2S)-1-([1-[(3R,4R)-3-Rtert-butyldimethylsily0oxyl-145-
(trifluoromethyppyrimidin-2-yllpiperidin-4-y1]-2-oxopyrrolidin-3-ylloxy)propan-
2-ylloxyl-
2-[(4-methoxyphenyOmethyll-4-(trifluoromethyl)pyridazin-3-one (60 mg, 0.08
mmol, 1
equiv) in TFA and TfOH (3 mL, 10:1) was stirred for 4 hours at 0 C and then
was diluted
with 10 mL of ice water. The pH adjusted to 7 by adding saturated aqueous
NaHCO3. The
resulting solution was extracted with 3 x 20 mL of ethyl acetate, and the
combined organic
layers were concentrated in vacuo. The crude product was purified by C18
reverse phase
chromatography eluting with water/CH3CN (1/1) to afford 7 mg (14% yield) of 5-
(((2S)-1-
((1-((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-y1)-2-
oxopyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-
one. LCMS
(ESI, m/z): 567.40 [M+H]+; 1FINMR (300 MHz, DMSO-d6) 6 13.21 (s, 1H), 8.69 (s,
2H),
8.31 -8.27 (m, 1H), 5.31 - 5.20 (m, 1H), 5.19- 5.12(m, 1H),4.89 - 4.81(m, 1H),
4.73 (d, J=
13.2 Hz, 1H), 4.14 - 3.69 (m, 4H), 3.64 - 3.39 (m, 2H), 3.17 - 3.09 (m, 2H),
3.05 - 2.91 (m,
1H), 2.80 - 2.69 (m, 1H), 2.27 - 2.18(m, 1H), 1.62 - 1.50 (m, 3H), 1.26 (d, J=
6.3 Hz, 3H).
Example 66: Synthesis of N-OS)-3-0(R)-2-oxo-1-(1-(5-(trifluoromethyppyrimidin-
2-
y1)piperidin-4-y1)pyrrolidin-3-ypoxy)-2-06-oxo-5-(trifluoromethyl)-1,6-
dihydropyridazin-4-y1)amino)propyl)acetamide.
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F3CJLN,PMB F3CAN,PMB
HN
NI A ____ HN.*1 NI 0
0
N-
_CNAD-CF3
0
0
F3CJL
I YE'
HNN 0
0
Step A
To a solution of 5-(((2S)-1-amino-3-(((R)-2-oxo-1-(1-(5-
(trifluoromethyppyrimidin-
2-yOpiperidin-4-yOpyrrolidin-3-y0oxy)propan-2-y0amino)-2-(4-methoxybenzyl)-4-
(trifluoromethyl)pyridazin-3(2H)-one (70 mg, 0.1 mmol, 1 equiv) in DCM (3 mL)
was added
DMAP (1 mg, 0.01 mmol, 0.1 equiv), acetic anhydride (15 mg, 0.15 mmol, 1.5
equiv) and
triethylamine (31 mg, 0.31 mmol, 3 equiv). The resulting solution was stirred
for 1 hour and
then was diluted with 60 mL of ethyl acetate. The mixture was washed with 3 x
20 ml of
water and then dried over anhydrous sodium sulfate and concentrated to afford
N-((S)-2-((1-
(4-methoxybenzy1)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-y1)amino)-3-
(((R)-2-
oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-y1)piperidin-4-y1)pyrrolidin-3-
y1)oxy)propyl)acetamide (66 mg, 71% yield) as a white solid. LCMS (ESI, m/z):
727.25
[M+H]+.
Step B
To a solution of N-((S)-2-((1-(4-methoxybenzy1)-6-oxo-5-(trifluoromethyl)-1,6-
dihydropyridazin-4-y1)amino)-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-
2-
y1)piperidin-4-y1)pyrrolidin-3-y1)oxy)propyl)acetamide (66 mg, 0.090 mmol, 1.0
equiv) in
TFA (1 mL) was added TfOH (0.1 mL), and the mixture was stirred for 1 hour.
The reaction
was quenched by the addition of 8 mL of water, and the pH was adjusted to 9
with saturated
aqueous Na2CO3. The resulting solution was extracted with 2 x 30 mL of ethyl
acetate. The
organic layers were combined, dried over anhydrous sodium sulfate and
concentrated in
vacuo. The residue was applied onto a C18 reverse phase column eluting with
water/CH3CN
(47153) to afford of N-((S)-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-
4-yl)pyrrolidin-3-yl)oxy)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-
yl)amino)propyl)acetamide (13 mg, 22% yield) as a white solid. LCMS (ESI,
m/z): 607.30
[M+F11+. 1FINMR (300 MHz, DMSO-d6) 6 12.49 (s, 1H), 8.69 (s, 2H), 8.14 (t, J=
5.9 Hz,
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1H), 7.98 (s, 1H), 6.55 ¨ 6.44 (m, 1H), 4.82 (d, J= 13.2 Hz, 2H), 4.21 ¨4.02
(m, 3H), 3.90 ¨
3.81 (m, 1H), 3.70¨ 3.61 (m, 1H), 3.30 ¨ 2.96 (m, 6H), 2.31 ¨ 2.15 (m, 1H),
1.81 (s, 3H),
1.81 ¨ 1.45 (m, 5H).
Example 67: Synthesis of 5-(42R,3R)-3-hydroxy-1-4(R)-2-oxo-1-(1-(5-
(trifluoromethyl)
pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)butan-2-yl)amino)-4-
(trifluoromethyl)
pyridazin-3(2H)-one
i\LICF3
N
0
Boc Boc Boc
*N1 /OH A /0Ts B p "
0
CF3
NO/
rOeThi 0
HCI
0 F3CAN,PMB
I I
H2N 0 D HNN 0
/
HO..< N¨
HO
0
F3C
JLNH
HN
HO 7
CF3
Step A
To a solution of tert-butyl (4R,5R)-4-(hydroxymethyl)-2,2,5-
trimethyloxazolidine-3-
.. carboxylate (4.0 g, 16 mmol, 1.0 equiv) in DCM (10 mL) was added 4-
toluenesulfonyl
chloride (3.7 g, 20 mmol, 1.2 equiv), DMAP (1.9 g, 16 mmol, 1.0 equiv) and
triethylamine
(3.3 g, 32.6 mmol, 2.0 equiv). The resulting solution was stirred for 4 hours
and then was
washed with 2 x 25 mL of saturated aqueous NaHCO3. The organic layers were
concentrated
and applied onto a silica gel column eluting with ethyl acetate/petroleum
ether (9/1) to afford
.. 5.8 g (89% yield) of tert-butyl (4R,5R)-2,2,5-trimethy1-4-
((tosyloxy)methyl)oxazolidine-3-
carboxylate as a yellow oil. LCMS (ESI, m/z): 344.05[M+Hr.
Step B
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To a solution of (R)-3-hydroxy-1-(1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidin-4-
yl)pyrrolidin-2-one (500 mg, 1.51 mmol, 1.0 equiv) in DMF (5 mL) at 0 C was
added NaH
(72 mg, 3.0 mmol, 2.0 equiv, 60% dispersion in oil). The mixture was stirred
for 10 minutes
and then tert-butyl (4R,5R)-2,2,5-trimethy1-4-((tosyloxy)methyl)oxazolidine-3-
carboxylate
(1.8 g, 4.5 mmol, 3.0 equiv) was added at 0 C. The reaction mixture stirred
an additional 6
hours at 40 C and then was concentrated and purified by silica gel
chromatography eluting
with ethyl acetate/petroleum ether (15/85) to afford 900 mg of tert-butyl
(4R,5R)-2,2,5-
trimethy1-4-((((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-
yl)pyrrolidin-3-
yl)oxy)methyl)oxazolidine-3-carboxylate as a yellow oil. LCMS (ESI, m/z):
558.25[M+Hr
.. Step C
A solution of tert-butyl (4R,5R)-2,2,5-trimethy1-4-((((R)-2-oxo-1-(1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-
yl)oxy)methyl)oxazolidine-3-
carboxylate (900 mg, 1.6 mmol, 1.0 equiv) in 4M HC1 in dioxane (10 mL) was
stirred for 6
hours, and then was concentrated to afford 850 mg of (R)-3-((2R,3R)-2-amino-3-
hydroxybutoxy)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-
yl)pyrrolidin-2-one
hydrogen chloride as a colorless oil that was carried on without further
purification. LCMS
(ESI, m/z): 418.10 [M+H1+.
Step D
To a solution of (R)-3-((2R,3R)-2-amino-3-hydroxybutoxy)-1-(1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one hydrogen
chloride (400 mg,
0.96 mmol, 1.0 equiv) in isopropanol (5 mL) was added 5-chloro-2-(4-
methoxybenzy1)-4-
(trifluoromethyl)pyridazin-3(2H)-one (366 mg, 1.15 mmol, 1.2 equiv) and N,N-
diisopropylethylamine (620 mg, 4.8 mmol, 5.0 equiv). The solution was stirred
for 6 hours at
80 C and was then concentrated and applied onto a silica gel column eluting
with ethyl
acetate/petroleum ether (95/5) to afford 170 mg (25% yield) of 5-(((2R,3R)-3-
hydroxy-1-
(((R)-2-oxo-1-(1-(5-(trifluoromethyppyrimidin-2-yOpiperidin-4-yOpyrrolidin-3-
y0oxy)butan-2-y0amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-
one as a
yellow solid. LCMS (ESI, m/z): 700.20 [M+Hr.
Step E
A solution of 5-(((2R,3R)-3-hydroxy-1-(((R)-2-oxo-1-(1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-3-yl)oxy)butan-2-
yl)amino)-2-(4-
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methoxybenzy1)-4-(trifluoromethyppyridazin-3(2H)-one (120 mg, 0.17 mmol, 1.0
equiv) in
TFA/TfOH (3 mL, 3:1) was stirred for 40 min at -10 C. The pH was adjusted to
¨6-7 with
saturated aqueous Na2CO3, and the resulting solution was extracted with 3 x 25
mL of ethyl
acetate. The organic layers were combined, dried over Na2SO4 and concentrated.
The crude
product was purified by C18 reverse phase chromatography eluting with
CH3CN/water to
afford 5-(((2R,3R)-3-hydroxy-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyppyrimidin-2-
yOpiperidin-4-yOpyrrolidin-3-y0oxy)butan-2-yl)amino)-4-
(trifluoromethyppyridazin-3(2H)-
one 55 mg (55% yield) as a white solid. LCMS (ESI, m/z): 580.20 [M+1-11+; 11-1-
NMR (300
MHz, DMSO-d6) 6 12.45 (s, 1H), 8.67 (s, 2H), 7.93 (s, 1H), 6.25-6.12 (m, 1H),
5.29 (d, J =
.. 4.1 Hz, 1H), 4.80 (d, J = 13.2 Hz, 2H), 4.15-4.07 (m, 2H), 3.96-3.82 (m,
3H), 3.69-3.61 (m,
1H), 3.28-2.94 (m, 4H), 2.25-2.16 (m, 1H), 1.79-1.53 (m, 5H), 1.07 (d, J= 6.2
Hz, 3H).
Example 68: Synthesis of 4-0R)-2-oxo-3-0S)-2-06-oxo-5-(trifluoromethyl)-1,6-
dihydropyridazin-4-yl)amino)propoxy)pyrrolidin-1-y1)-1-(5-
(trifluoromethyppyrimidin-
2-y1)piperidine-3-carboxamide
o o
H2N HO......A HO_j., ...
N \N¨Boc N \NH.HCI C
0.....--......õ-N,Boc __ A ----I / B __ -----../ ____ /
..-
0 0
0 0 0
_/ _/
HO
HO N¨( CF3 D HO
N 3 CF
i E
---.../
0 l\J
0
0 /
¨/ OH ONy
NH2 N
Boc, CF3
NH NH2 HCI
0 0
F
G c)----"NNC) H
>
_______________ ..- ___________________ _
NH2
1
\1 C
- 3F
0
0
F3C)-LN, PMB
I I F3C.)(NH
HNN 0 1 I
HNN
I 0
N sõ,=04.6 ___________________________________________ N4ND--CF3
N
0
NH2 o
NH2
Step A
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To a solution of 1-(tert-butyl) 3-ethyl 4-aminopiperidine-1,3-dicarboxylate
(16.0 g,
58.7 mmol, 1.00 equiv) in DCM (200 mL) was added AcOH (5.29 g, 88.1 mmol, 1.50
equiv)
and (R)-2-(2,2-dimethy1-5-oxo-1,3-dioxolan-4-yOacetaldehyde (10.2 g, 64.6
mmol, 1.1
equiv). The resulting solution was stirred for 5 hours at room temperature,
and then STAB
(24.9 g, 117 mmol, 2.0 equiv) was added, and the reaction mixture was stirred
for an
additional 45 hours. The solution was quenched by the addition of 100 mL of
ice water, and
the pH was adjusted to 8 with 1% aqueous NaOH. The solution was extracted with
300 mL of
DCM. The organic layers were combined, dried over anhydrous sodium sulfate,
and
concentrated in vacuo. The crude product was applied onto a silica gel column
eluting with
.. ethyl acetate/petroleum ether (1/9) to afford 5.7 g (27% yield) of 1-(tert-
butyl) 3-ethyl 4-((R)-
3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1,3-dicarboxylate as a brown oil.
Step B
A solution of 1-(tert-butyl) 3-ethyl 4-((R)-3-hydroxy-2-oxopyrrolidin-1-
yl)piperidine-
1,3-dicarboxylate (5.70 g, 16.0 mmol, 1.0 equiv) in 4N HC1 in dioxane (40 mL)
was stirred
for 20 hours. The resulting mixture was concentrated in vacuo to afford 5 g of
ethyl 4-((R)-3-
hydroxy-2-oxopyrrolidin-1-yl)piperidine-3-carboxylate hydrochloride as a brown
solid that
was carried on without further purification.
Step C
To a solution of ethyl 4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-3-
carboxylate hydrochloride (5.00 g, 17.1 mmol, 1.0 equiv) in DMF (40 mL) was
added 2-
chloro-5-(trifluoromethyppyrimidine (3.12 g, 17.1 mmol, 1.0 equiv) and K2CO3
(7.08 g, 51.2
mmol, 3.0 equiv). The resulting solution was stirred for 1 hour at 60 C and
was concentrated
in vacuo and purified by reverse phase chromatography eluting with water/CH3CN
(9/11) to
afford 1.2 g(17% yield) of ethyl 4-((R)-3-hydroxy-2-oxopyrrolidin-1-y1)-1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidine-3-carboxylate as a yellow solid.
LCMS (ESI,
m/z): 403.2 [M+1-11+.
Step D
To a solution of ethyl 4-((R)-3-hydroxy-2-oxopyrrolidin-1-y1)-1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidine-3-carboxylate (558 mg, 1.39 mmol,
1.0 equiv) in
Et0H (5 mL) and water (1 mL) was added NaOH (111 mg, 2.78 mmol, 2.0 equiv).
The
resulting solution was stirred for 15 hours. The pH was adjusted to 5 with HC1
(2 M) and was
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concentrated in vacuo. The residue was applied onto a silica gel column
eluting with
water/CH3CN (5:1) to afford 420 mg (81% yield) of 4-((R)-3-hydroxy-2-
oxopyrrolidin-1-y1)-
1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidine-3-carboxylic acid as a yellow
solid. LCMS
(ESI, m/z): 375.10 [M+1-11+.
Step E
To a solution of 4-((R)-3-hydroxy-2-oxopyrrolidin-1-y1)-1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidine-3-carboxylic acid (420 mg, 1.1
mmol, 1.0 equiv)
in DMF (5 mL) was added N,N-diisopropylethylamine (290 mg, 2.2 mmol, 2.0
equiv),
NH4C1 (90 mg, 1.7 mmol, 1.5 equiv) and HATU (640 mg, 1.7mmo1, 1.5 equiv). The
resulting
solution was stirred for 1.5 hours and then applied onto a reverse phase C18
column eluting
with water/CH3CN (5:1) to afford 400 mg (95% yield) of 4-((R)-3-hydroxy-2-
oxopyrrolidin-
1-y1)-1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidine-3-carboxamide as a
yellow solid.
LCMS (ESI, m/z): 374.10 [M+Hr.
Step F
To a solution of 4-((R)-3-hydroxy-2-oxopyrrolidin-1-y1)-1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidine-3-carboxamide (400 mg, 1.1 mmol,
1.0 equiv) in
DMF (20 mL) at 0 C was added NaH (86 mg, 2.2 mmol, 2.0 equiv, 60% dispersion
in oil).
After 15 minutes, a solution of tert-butyl (4S)-4-methy1-2,2-dioxo-
1,21ambda6,3-
oxathiazolidine-3-carboxylate (265 mg, 1.12 mmol, 1.0 equiv) in DMF (2 mL) was
added,
and the mixture stirred for 1 hour. The reaction was quenched by the addition
of 2 mL of
saturated aqueous sodium bicarbonate. The resulting mixture was concentrated
and applied
onto a reverse phase column eluting with water/CH3OH (11:9) to afford 330 mg
(48% yield)
of tert-butyl ((2S)-1-(((3R)-1-(3-carbamoy1-1-(5-(trifluoromethyppyrimidin-2-
yOpiperidin-4-
y1)-2-oxopyrrolidin-3-y0oxy)propan-2-yOcarbamate as a yellow solid. LCMS (ESI,
m/z):
531.30 [M+H1+.
Step G
A solution of tert-butyl 42S)-1-(43R)-1-(3-carbamoyl-1-(5-
(trifluoromethyppyrimidin-2-yOpiperidin-4-y1)-2-oxopyrrolidin-3-y0oxy)propan-2-
yOcarbamate (330 mg, 0.62 mmol, 1.0 equiv) in 4N HC1 in dioxane (5 mL) was
stirred for 1
hour, and then was concentrated in vacuo to afford 305 mg (66% yield) of 4-
((R)-3-((S)-2-
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aminopropoxy)-2-oxopyrrolidin-1-y1)-1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidine-3-
carboxamide hydrochloride as alight yellow solid. LCMS (ESI, m/z): 431.20 [M+1-
11+.
Step H
To a solution of 4-((R)-3-((S)-2-aminopropoxy)-2-oxopyrrolidin-1-y1)-1-(5-
(trifluoromethyl)pyrimidin-2-yl)piperidine-3-carboxamide hydrochloride (280
mg, 0.60
mmol, 1.0 equiv) in CH3CN (5 mL) was added N,N-diisopropylethylamine (280 mg,
2.2
mmol, 3.6 equiv) and 5-chloro-2-[(4-methoxyphenyOmethy11-4-
(trifluoromethyl)pyridazin-3-
one (201 mg, 0.63 mmol, 1.1 equiv). The solution was stirred for 1 hours at 80
C, and then
was concentrated in vacuo. The crude product was applied onto a reverse phase
C18 column
eluting with water/CH3CN (1/1) to afford 290 mg (63% yield) of 4-((R)-3-((S)-2-
41-(4-
methoxybenzy1)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-
y1)amino)propoxy)-2-
oxopyrrolidin-1-y1)-1-(5-(trifluoromethyl)pyrimidin-2-y1)piperidine-3-
carboxamide as a
yellow solid. LCMS (ESI, m/z): 713.25 [M+H1+.
Step I
A solution of 4-((R)-3-((S)-2-((1-(4-methoxybenzy1)-6-oxo-5-(trifluoromethyl)-
1,6-
dihydropyridazin-4-y0amino)propoxy)-2-oxopyrrolidin-1-y1)-1-(5-
(trifluoromethyl)pyrimidin-2-y1)piperidine-3-carboxamide (570 mg, 0.80 mmol,
1.0 equiv) in
TFA/TfOH (5 mL, 10:1) was stirred for 1 hour. The reaction was quenched by the
addition of
15 mL of ice water, and the pH was adjusted to ¨7-8 with aqueous saturated
Na2CO3. The
solution was extracted with 3 x 60 mL of DCM. The organic layers were
combined, dried
over anhydrous sodium sulfate and concentrated in vacuo. The residue was
purified by
reverse phase chromatography eluting with water/CH3CN (3/2) to afford 314 mg
(66% yield)
of 4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-
yl)amino)propoxy)pyrrolidin-1-y1)-1-(5-(trifluoromethyl)pyrimidin-2-
yl)piperidine-3-
carboxamide as a yellow solid. LCMS (ESI, m/z): 593.15 [M+1-11+;11-1NMR (400
MHz,
DMSO-d6) 6 12.46 (s, 1H), 8.74 (s, 2H), 7.95 (d, J= 7.9 Hz, 1H), 7.53-7.48 (m,
1H), 6.99 (s,
1H), 6.37-6.29 (m, 1H), 4.89-4.76 (m, 2H), 4.33 ¨ 4.01 (m, 3H), 3.86-3.73 (m,
1H), 3.63-3.53
(m, 1H), 3.29-3.20 (m, 1H), 3.15-3.00 (m, 3H), 2.68 ¨ 2.53 (m, 1H), 2.31-2.12
(m, 1H), 1.82
¨ 1.56 (m, 3H), 1.19-1.13 (m, 3H).
Example 69: Synthesis of 4-0R)-2-oxo-3-0S)-2-06-oxo-5-(trifluoromethyl)-1,6-
dihydropyridazin-4-yllamino)propoxy)pyrrolidin-l-y1)-1-(5-
(trifluoromethyppyrimidin-
2-y1)piperidine-3-carbonitrile.
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0 0
j=L F3CJL NH F3C NH
HNN 0 HN'' 0
4ND¨CF3 ___________________________________ - N¨
N
0 NC
NH2
To a solution of 4-((R)-2-oxo-3-((S)-2-46-oxo-5-(trifluoromethyl)-1,6-
dihydropyridazin-4-y1)amino)propoxy)pyrrolidin-1-y1)-1-(5-
(trifluoromethyl)pyrimidin-2-
y1)piperidine-3-carboxamide (320 mg, 0.54 mmol, 1.0 equiv) in water (22 mL)
and CH3CN
(27 mL) was added palladium chloride (133 mg, 0.75 mmol, 1.4 equiv). The
resulting
solution was stirred overnight at 80 C and then was extracted with 4 x 30 mL
of ethyl
acetate. The organic layers were combined, dried over anhydrous sodium
sulfate, and
concentrated. The residue was applied onto a C18 reverse phase column eluting
with
water/CH3CN (1/1) to afford 15 mg (5% yield) of 4-((R)-2-oxo-3-((S)-2-((6-oxo-
5-
(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)pyrrolidin-l-y1)-1-
(5-
(trifluoromethyl)pyrimidin-2-y1)piperidine-3-carbonitrile as a white solid.
LCMS (ESI, m/z):
575.25 [M+H1+; 11-1NMR (400 MHz, DMSO-d6) 6 12.46 (s, 1H), 8.85 (s, 2H), 7.95
(d, J =
3.6 Hz, 1H), 6.32 (br, 1H), 5.13 ¨ 5.01 (m, 1H), 4.93 ¨4.76 (m, 1H), 4.46 ¨
4.34 (m, 1H),
4.28 ¨4.12 (m, 2H), 3.86 ¨ 3.75 (m, 1H), 3.68 ¨ 3.58 (m, 1H), 3.49 ¨ 3.39 (m,
1H), 3.26 ¨
3.08 (m, 3H), 2.32 ¨ 2.24 (m, 1H), 1.99¨ 1.58 (m, 3H), 1.28¨ 1.13 (m, 4H).
Example A. Enzymatic Assay for Inhibition of PARP7
Displacement of Probe A, a biotinylated probe binding to the TIPARP active
site, was
measured using a time-resolved fluorescence energy transfer (TR-FRET) assay.
20 nL of a
dose response curve of each test compound was spotted in black 384-well
polystyren.e
proxiplates (Perkin Elmer) using a Mosquito (TTP Labtech). Reactions were
performed in a
8 volume by adding 6 ut of TIPARP and Probe A in assay buffer (20 /TIM
HEPES pH =
8, 100 rni'vl NaCI, 0.1% bovine serum albumin, 2 rriM DTT and 0.002% Tween20),
incubating with test compound at 25 C for 30 mm, then adding 21.1.1L of
lThight-anti 6xHis
and LANCE Eu-W1024 labeled streptavidin (Perkin Elmer). The final
concentrations of
TIPARP and Probe A were 6 nM and 2 n1\4, respectively. The final concentration
of ',Tight:-
anti 6xHis and LANCE Eu-W1024 labeled streptavidin were 4 nM and 0.25111\4,
respectively. Reactions were incubated at 25 'V for an additional 30 min, then
read on an
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Envision platereader equipped with a LANCE/DELFIA top mirror (Perkin Elmer)
using
excitation of 320 nin and emission of 615 nin and 665 n114 with a 90 pts
delay. The ratio of
the 665/615 nm emission were calculated for each well to determine the amount
of complex
of TIPARP and Probe Am each well. Control wells containing a negative control
of 0.25%
MIS vehicle or a positive control of 100 itM 5-(5-(piperidin-4-
yloxy)isoindolin-2-y1)-4-
(trifluoromethyl)pyridazin-3(2H)-one were used to calculate the % inhibition
as described
below:
TRF TRF
cmpd intn
% inhibition = 100 x
T R Erna, TREmin
where TRFcmpd is the TR-FRET ratio from the compound treated well, TREllin is
the TR-
IO FRET ratio from the 5-(5-(piperidin-4-yloxy)isoindolin-2-y1)-4-
(trifluoromethyl)pyridazin-
3(2H)-one -treated positive control well and TRFmax is the TR-FRET ratio from
the DMS0-
treated negative control well.
The % inhibition values were plotted as a function of compound concentration
and the
following 4-parameter fit was applied to derive the IC5o values:
(Top ¨ Bottom)
Y=bottOm ___________________
\Hitt Coe f ficient
where top and bottom are normally allowed to float, but may be fixed at 100 or
0 respectively
in a 3-parameter fit. The Hill Coefficient is normally allowed to float but
may also be fixed at
1 in a 3-parameter fit. Y is the % inhibition and X is the compound
concentration.
S_snthesis of Probe A
0
NH
F3c /N
0
)LNH
HN.
0
0
Step A
A solution of 5-chloro-4-(trifluoromethyl)-24[2-(trimethylsilypethoxylmethy11-
2,3-
dihydropyridazin-3-one (2.8 g, 8.52 mmol, 1.00 equiv), 2,3-dihydro-1H-isoindo1-
5-ol
hydrobromide (4.27 g, 19.76 mmol, 1.00 equiv), and TEA (10 mL) in ethanol (40
mL) was
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stirred for 1 h at 60 C. The resulting solution was extracted with 2 x 100 mL
of ethyl acetate
and the organic layers combined and concentrated under reduced pressure to
afford 4.5 g of
5-(5-hydroxy-2,3-dihydro-1H-isoindo1-2-y1)-4-(trifluoromethyl)-2-[[2-
(trimethylsilypethoxylmethyll-2,3-dihydropyridazin-3-one as a yellow oil.
LCMS: [M+I-11+
428.23.
Step B
A solution of 5-(5-hydroxy-2,3-dihydro-1H-isoindo1-2-y1)-4-(trifluoromethyl)-2-
[[2-
(trimethylsilypethoxylmethyl]-2,3-dihydropyridazin-3-one (4.5 g, 10.53 mmol,
1.00 equiv),
tert-butyl 4-iodopiperidine-1-carboxylate (20 g, 64.28 mmol, 8.00 equiv),
potassium
carbonate (15 g, 108.53 mmol, 10.00 equiv), and DMF (50 mL) was stirred for 2
days at 80
C. The resulting solution was extracted with 2 x 200 mL of ethyl acetate and
the organic
layers combined and concentrated under reduced pressure. The residue was
applied onto a
silica gel column eluting with ethyl acetate/petroleum ether to afford tert-
butyl 4-([246-oxo-
5-(trifluoromethyl)-14[2-(trimethylsilypethoxylmethy11-1,6-dihydropyridazin-4-
y11-2,3-
dihydro-1H-isoindo1-5-ylloxy)piperidine-1-carboxylate (2 g, 31%) as a yellow
oil. LCMS:
[M-411+ 611.15.
Step C
A solution of tert-butyl 4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-
(trimethylsilyl)ethoxylmethy11-1,6-dihydropyridazin-4-y11-2,3-dihydro-1H-
isoindo1-5-
.. ylloxy)piperidine-1-carboxylate (2 g, 3.27 mmol, 1.00 equiv), dioxane/HC1
(5 mL), and
dioxane (45 mL) was stirred for 6 h at 25 C. The resulting mixture was
concentrated under
reduced pressure. The residue was applied onto a silica gel column and eluted
with ethyl
acetate/petroleum ether to afford 1 g of 5-[5-(piperidin-4-yloxy)-2,3-dihydro-
1H-isoindo1-2-
y11-4-(trifluoromethyl)-2-[[2-(trimethylsilypethoxylmethyl]-2,3-
dihydropyridazin-3-one as a
.. yellow oil. LCMS: [M+I-11+ 511.28.
Step D
A solution of 545-(piperidin-4-yloxy)-2,3-dihydro-1H-isoindo1-2-y11-4-
(trifluoromethyl)-2-[[2-(trimethylsilypethoxylmethyll-2,3-dihydropyridazin-3-
one (1 g, 1.96
mmol, 1.00 equiv), tert-butyl 2-chloroacetate (450 mg, 2.99 mmol, 3.00 equiv),
DIPEA (5
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mL), and dichloromethane (10 mL) was stirred overnight at 25 C. The residue
was purified
by C18 reverse phase chromatography eluting with H20/CH3CN to afford tert-
butyl 2-[4-([2-
[6-oxo-5-(trifluoromethyl)-14[2-(trimethylsilypethoxylmethy11-1,6-
dihydropyridazin-4-y11-
2,3-dihydro-1H-isoindo1-5-ylloxy)piperidin-1-yllacetate (540 mg, 44%) as a
yellow oil.
LCMS: [M+I-11+ 625.20.
Step E
A solution of ter t-butyl 2-[4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-
(trimethylsilypethoxylmethy11-1,6-dihydropyridazin-4-y11-2,3-dihydro-1H-
isoindo1-5-
ylloxy)piperidin-1-yllacetate (540 mg, 0.86 mmol, 1.00 equiv) and dioxane/HC1
(8 mL) was
stirred overnight at 25 C. The resulting mixture was concentrated under
reduced pressure.
The residue was purified by C18 reverse phase chromatography eluting with
H20/CH3CN to
afford 200 mg (53%) of 2-[4-([246-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-
4-y11-2,3-
dihydro-1H-isoindol-5-ylloxy)piperidin-1-yllhydrochloride as a white solid.
LCMS: [M+Hr
439.31.
Step F
A solution of 5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-dlimidazolidin-4-
yllpentanoic acid (reagent was purchased from Beijing Dragon Rui Trading
Company, 976
mg, 3.99 mmol, 1.00 equiv), DIPEA (1.55 g, 11.99 mmol, 3.00 equiv), HATU (1.82
g, 4.79
mmol, 1.20 equiv), tert-butyl N-(6-aminohexyl)carbamate (864 mg, 3.99 mmol,
1.00 equiv)
in DMF (15 mL) was stirred overnight at 25 C. The reaction was then quenched
by the
addition of 50 mL of water. The solids were collected by filtration to afford
1.5 g (85%) of
tert-butyl N-(6-[5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-dlimidazolidin-
4-
yllpentanamidolhexyl)carbamate as a white solid. LCMS: [M+1-11+ 443.26.
Step G
A solution of tert-butyl N-(645-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-
dlimidazolidin-4-yllpentanamidolhexyl)carbamate (800 mg, 1.81 mmol, 1.00
equiv) in
hydrogen chloride/dioxane (20 mL) was stirred overnight at 25 C. The
resulting mixture
was concentrated under reduced pressure to afford 600 mg (88%) of 5-
[(3aS,4S,6aR)-2-0xo-
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hexahydro-1H-thieno[3,4-dlimidazolidin-4-yll-N-(6-aminohexyl)pentanamide
hydrochloride
as a gray crude oil. LCMS: [M+Hl+ 343.21.
Step H
A solution of 2-[4-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-y1]-
2,3-dihydro-
1H-isoindo1-5-ylloxy)piperidin-1-yllhydrochloride (175 mg, 0.40 mmol, 1.00
equiv), DIPEA
(258 mg, 2.00 mmol, 5.00 equiv), HATU (228 mg, 0.60 mmol, 1.50 equiv), 5-
[(3aS,4S,6aR)-
2-oxo-hexahydro-1H-thieno[3,4-d]imidazolidin-4-yll-N-(6-aminohexyl)pentanamide
hydrochloride (228 mg, 0.60 mmol, 1.50 equiv) in DMF (3 mL) was stirred for 4
h at 25 C.
The crude product was purified by C18 reverse phase chromatography eluting
with
.. H20/CH3CN to afford 5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-
dlimidazolidin-4-
yll-N-(6-[244-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-y1]-2,3-
dihydro-1H-
isoindol-5-ylloxy)piperidin-1-yllacetamidolhexyl)pentanamide as a white solid
(118.3 mg,
39%). LCMS: [M+Hl+ 763.35.
11-1NMR (DMSO-d6, 400 MHz) (5: 12.52 (s, 1H), 7.98 (s, 1H), 7.81 - 7.68 (m,
2H), 7.26 (d, J
= 8.4 Hz, 1H), 7.00 (d, J= 2.2 Hz, 1H), 6.91 (dd, J = 8.4, 2.3 Hz, 1H), 6.45 -
6.39 (m, 1H),
6.36 (s, 1H), 4.91 (d, J= 6.1 Hz, 4H), 4.45 (m, 1H), 4.26 (m, 1H), 4.17 - 4.08
(m, 1H), 3.14 -
2.96 (m, 5H), 2.91 (s, 2H), 2.82 (dd, J= 12.4, 5.1 Hz, 1H), 2.73 -2.63 (m,
2H), 2.58 (d, J=
12.4 Hz, 1H), 2.33 (ddd, J= 11.8, 9.4, 3.1 Hz, 2H), 2.11 - 1.90 (m, 4H), 1.76-
1.54 (m, 3H),
1.57 - 1.20 (m, 13H).
ICso data for the Example compounds is provided below in Table A-1 ("+" is
<0.1
[tM; "++" is > 0.1 [tM < 1 [tM; and "+++" is? 1 [tM).
Table A-1. ICso Data for Example Compounds
Example
ICso
No.
1
2
3
4
5
6
7
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8 +
9 +
10A ++
10B +
11 +
12 +
13A ++
13B +
14A +++
14B +
15A ++
15B +
16 +
17A ++
17B +
18A ++
18B +
19A ++
19B +
20A +
20B +
21 ++
22A ++
22B +
23 ++
24 +
25 +
26A +++
26B +
26C +++
26D ++
27 +
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28 +
29 +
30 +
31A +
31B ++
32 +
33A +
33B +
34A +
34B +
35A +++
35B +
36A +
36B +
37A +++
37B +
38A +
38B +
39A +
39B +
40A +
40B +
41 +
42 +
43 +
44 +
45 +
46A ++
46B +
47A ++
47B +
48A +
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48B +
49A ++
49B +
50A ++
50B +
51A ++
51B +
52A ++
52B +
53 +
54 +
55A +++
55B +
56A +++
56B +
57 +
58 +
59 +
60 +
61 +
62 +
63 +
64A +
64B +
65 +
66 +
67 +
68 +
69 +
Example B. PARP7 Inhibitors' Affect on Tumor Growth in Human Lung Cancer
Models NCI-H1373
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Figure 1 illustrates that PARP7 inhibitors significantly reduce tumor growth
in human
lung cancer models NCI-H1373. In this study, CB-17 SCID mice were inoculated
subcutaneously at the right flank with NCI-H1373 cells for tumor development.
Six days
after tumor inoculation, 20 mice with tumor size ranging from 105-160 mm3
(average tumor
.. size 132 mm3) were selected and assigned into 2 groups using stratified
randomization with
mice in each group based upon their tumor volumes. The treatments were started
from the
next day post randomization (defined randomization day as day 0), and the mice
were treated
with vehicle (50 % Labrasol), the compound of Example 57 (100 mg/kg PO. QD*28
days).
The tumor sizes were measured three times per week during the treatment. The
entire study
10 was terminated on day 28.
Mean tumor volume and SEM were plotted (Figure 1). Statistical significance,
calculated using two-way ANOVA combined with Bonferroni post-test in which
treatment
group was compared to vehicle control, is indicated by an asterisk.
Various modifications of the invention, in addition to those described herein,
will be
apparent to those skilled in the art from the foregoing description. Such
modifications are
also intended to fall within the scope of the appended claims. Each reference,
including all
patent, patent applications, and publications, cited in the present
application is incorporated
herein by reference in its entirety.
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